Compositions and methods for treating lysosomal disorders

ABSTRACT

The present invention provides compositions and methods for treating lysosomal disorders using a class of substituted imidazole derivatives or compounds.

RELATED APPLICATIONS

T is application claims the benefit of U.S. Provisional PatentApplication No. 60/991,136, filed Nov. 29, 2007, and U.S. ProvisionalPatent Application No. 61/095,825, filed Sep. 10, 2008, the disclosuresof which are herein incorporated by reference in their entirety.

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

The present invention was made with the support of the Canadiangovernment under Grant number MT 13073 by the Canadian Institutes ofHealth Research.

BACKGROUND

Glycosphingolipid (GSL) levels affect a variety of cell functions, suchas growth, differentiation, adhesion between cells or between cells andmatrix proteins, binding of microorganisms and viruses to cells, andmetastasis of tumor cells. Glycosphingolipids (GSLs) are derived fromglucosylceramide (GlcCer), and the GlcCer precursor, ceramide. GSLs andtheir precursors have a role in the differentiation or inhibition ofcell growth (Bielawska, et al., FEBS Letters 307:211-214 (1992)) and maybe involved in functioning of vitamin D₃, tumor necrosis factor α,interleukins, and apoptosis (programmed cell death). The sphingols(sphingoid bases), precursors of ceramide, and products of ceramidecatabolism, have also been shown to influence many cell systems,possibly by inhibiting protein kinase C(PKC).

Glucosylceramide is made on the outer leaflet of the Golgi through theaction of GlcCer synthase. GlcCer is thought to be then transferred tothe lumen of the Golgi for glycotransferases to be able to access GlcCerto generate more complex GSLs. The ABC transporter, multiple drugresistance protein 1 (MDR1, P-glycoprotein) is believed to promote GSLsynthesis. MDR1 has been shown to translocate glucosylceramide from thecytosolic to the luminal Golgi surface.

The importance of GSL metabolism is underscored by the seriousness ofdisorders resulting from defects in GSL metabolizing enzymes. Forexample, Tay-Sachs, Gaucher's, and Fabry's diseases, resulting fromenzymatic defects in the GSL degradative pathway and the accumulation ofGSL in the patient, all have severe clinical manifestations. Anotherexample of the importance of GSL function is seen in a mechanism bywhich blood cells, whose surfaces contain selectin, can, under certainconditions, bind to GSLs in the blood vessel walls and produce acute,life-threatening inflammation (Alon et at, J. Immunol., 54:5356-5366(1995)).

Because of the significant impact GSLs have on several biochemicalprocesses, there remains a need for compounds to modulate GSL synthesisand metabolism when the processes become awry, resulting in diseases anddisorders. Thus, it is desirable to provide compounds and therapeuticmethods to treat conditions and diseases associated with altered GSLlevels and/or GSL precursor levels. The present invention providescompositions and methods that satisfies these needs and provides relatedadvantages as well.

SUMMARY

The present invention provides methods and compositions for reducingglycolipid synthesis in a subject suffering from a disease other thancancer comprising administering to the subject an effective amount of acompound of Formula 1

in the form of a free compound or its pharmaceutically acceptablepro-drug, metabolite, analogue, derivative, solvate or salt wherein thesubstituents R₁, R₂, R₃, and R₄ are defined as described in (a) and (b)below:(a) when R₁ is selected from the group consisting of:

-   -   (i) substituted C₁₋₁₁ alkyl or substituted C₂₋₁₁ alkenyl,        wherein the substituents are selected from the group consisting        of hydroxy, C₁₋₆ alkyloxy; or    -   (ii) mono-, di-, and tri-substituted aryl-C₀₋₁₁ alkyl wherein        aryl is selected from the group consisting of phenyl, furyl,        thienyl wherein the substituents are selected from the group        consisting of:        -   (a) phenyl, trans-2-phenylethenyl, 2-phenylethynyl,            2-phenylethyl, wherein the said phenyl group is mono- or            disubstituted with a member selected from the group            consisting of hydroxy, halo, C₁₋₄ alkyl and C₁₋₄ alkyloxy,        -   (b) substituted C₁₋₆ alkyl, substituted C₂₋₆ alkyloxy,            substituted C₂₋₆ alkylthio, substituted C₂₋₆ alkoxycarbonyl,            wherein the substituents are selected from the group            consisting of C₁₋₄ alkoxy, and C₁₋₆ alkylthio; and

(c) C₁₋₁₁ CO₂R₅, C₁₋₁₁CONHR₅, trans-CH═CHCO₂R₅, or trans-CH═CHCONHR₅wherein R₅ is C₁₋₁₁ alkyl, or phenyl C₁₋₁₁ alkyl, C₁₋₆alkoxycarbonylmethyleneoxy;

then R₂ and R₃ are each independently selected from the group consistingof mono-, di, and tri-substituted phenyl wherein the substituents areindependently selected from:

-   -   (i) substituted C₁₋₆ alkyl,    -   (ii) substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy, substituted        C₃₋₆ alkenyloxy,    -   (iii) substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆        alkyl)amino,    -   (iv) C₃₋₆ alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆        alkenyl-amino, di(substituted C₃₋₆ alkenyl)amino,    -   (v) pyrrolidino, piperidino, morpholino, imidazolyl, substituted        imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆        alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino,        4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino        C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆        alkenyl)piperazino,        wherein the substituents are selected from the group consisting        of:    -   (a) hydroxy, C₁₋₄ alkylalkoxy, C₁₋₆ alkylamino    -   (b) C₃₋₆ alkenyloxy, C3-6 alkenylamino, or    -   (c) pyrrolidino, piperidino, morpholino, imidazolyl, substituted        imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆        alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino,        4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino        C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆        alkenyl)piperazino,        or R₂ and R₃ taken together forming an aryl group or substituted        aryl, wherein the substituents are defined as above in (i)-(v);        and R₄ is selected from the group consisting of:    -   (i) hydrogen;    -   (ii) substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the        substituents are independently selected from the group        consisting of hydrogen, hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio,        C₁₋₄ alkylamino, phenyl-C₁₋₆ alkylamino, C₁₋₆ alkoxycarbonyl; or    -   (iii) substituted aryl C₀₋₁₁ alkyl wherein the aryl group is        selected from phenyl, imidazolyl, furyl, thienyl in which the        substituents are selected from A(a-c); or        (b) when R₁ is selected from the group consisting of:

Mono-, di-, and tri-substituted aryl-C₀₋₆ alkyl wherein aryl is selectedfrom the group consisting of phenyl, thienyl, and the substituents areselected from the group consisting of:

-   -   (a) trans-2-substituted benzimidazolylethenyl,        trans-2-substituted benzoxazolylethenyl, trans-2-substituted        benzthiazolylethenyl, in which the substituents are selected        from the group consisting of hydrogen, hydroxy, halo,        trihalomethyl, C₁₋₄ alkyl and C₁₋₄ alkyloxy, C₁₋₄        alkyloxycarbonyl, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₃₋₆        alkenylamino, di(C₃₋₆ alkenyl)amino, C₁₋₄ alkyloxy-C₄        alkylamino, substituted C₁₋₄ alkyl and C₁₋₄ alkyloxy,        substituted C₁₋₄ alkyloxycarbonyl, substituted C₁₋₄ alkylamino,        di(substituted C₁₋₄ alkyl)amino, substituted C₃₋₆ alkenylamino,        di(substituted C₃₋₆ alkenyl)amino, wherein the substituents are        as defined above,    -   (b) trans-2-cyano ethenyl, trans-2-alkylsulfonyl ethenyl,        trans-2-alkenylsulfonyl ethenyl, trans-2-substituted        alkylsulfonyl ethenyl, trans-2-substituted alkenylsulfonyl        ethenyl, in which the substituents are defined above,    -   (c) C₁₋₆ CO₂R₅, trans-CH═CHCO₂R₅, C₁₋₆CONHR₅, or        trans-CH═CHCONHR₅, wherein R₅ is C₁₋₆ alkoxy C₂₋₆ alkyl, amino        C₂₋₆ alkyl, C₁₋₆ alkylamino C₂₋₆ alkyl, di(C₁₋₆ alkyl)amino C₂₋₆        alkyl, C₁₋₆ alkylthio C₂₋₆ alkyl, substituted C₁₋₆ alkoxy C₂₋₆        alkyl, substituted C₁₋₄ alkylamino C₂₋₆ alkyl, di(substituted        C₁₋₆ alkyl)amino C₂₋₆ alkyl, substituted C₁₋₆ alkylthio C₂₋₆        alkyl, in which the substituents are selected from the group        consisting of pyrrolidino, piperidino morpholino, piperazino,        4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆        alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆        alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆ alkyl)piperazino,        4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino, imidazolyl,        oxazolyl, thiazolyl,    -   (d) C₁₋₆CONR₆R₇, or trans-CH═CHCONR₆R₇, wherein R₆ and R₇ are        independently selected from the group consisting of C₁₋₆ alkyl,        phenyl C₁₋₆ alkyl, C₁₋₆ alkoxycarbonylmethyleneoxy, hydroxy C₂₋₆        alkyl, C₁₋₆ alkyloxy C₂₋₆ alkyl, amino C₂₋₆ alkyl, C₁₋₆        alkylamino C₂₋₆ alkyl, di(C₁₋₆ alkyl)amino C₂₋₆ alkyl, C₁₋₆        alkylthio C₂₋₆ alkyl, substituted C₁₋₆ alkoxy C₂₋₆ alkyl,        substituted C₁₋₆ alkylamino C₂₋₆ alkyl, di(substituted C₁₋₆        alkyl)amino C₂₋₆ alkyl, substituted C₁₋₆ alkylthio C₂₋₆ alkyl,        wherein the substituents are selected from the group consisting        of pyrrolidino, piperidino, morpholino, piperazino, 4-N—C₁₋₆        alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy        C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino,        4-N—(C₁₋₆ alkylamino C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino        C₃₋₆ alkenyl)piperazino, imidazolyl, oxazolyl, thiazolyl,    -   (e) R₇ C(O) C₁₋₆ alkyl, R₇ C(O)C₂₋₆ alkenyl, in which R₇ is        defined as above [2(d)],    -   (f) HO—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇—O—C₁₋₆ alkyl-C₂₋₆ alkenyl,        R₇NH—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl,        R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C(O)—O—C₁₋₆        alkyl-C₂₋₆ alkenyl, R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl,        R₇—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, wherein R₆ and R₇ is defined        as above [2(d)],    -   (g) R₇—O—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl, R₇NH—C₀₋₃ alkyl-C₃₋₆        cycloalkan-1-yl, R₆R₇N—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl,        R₇NH—C(O)—O—C₀₋₃ C₃₋₆ cycloalkan-1-yl, R₆R₇N—C(O)—O—C₀₋₃        alkyl-C₃₋₆ cycloalkan-1-yl, R₇O—C(O)—O—C₀₋₃ alkyl-C₃₋₆        cycloalkan-1-yl, R—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl,        R₇O—C(O)—Co-3 alkyl-C₃₋₆ cycloalkan-1-yl, wherein R₇ and is        defined as above [B(d)];        then R₂ and R₃ are each independently selected from the group        consisting of:

-   (1) hydrogen, halo, trihalomethyl, C₁₋₆ alkyl, substituted C₁₋₆    alkyl, C₂₋₆ alkenyl, substituted C₁₋₆ alkenyl, C₁₋₆ alkyloxy,    substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy, substituted C₃₋₆    alkenyloxy, C₁₋₆ alkylamino, substituted C₁₋₆ alkylamino, C₃₋₆    alkenylamino, substituted C₃₋₆ alkenylamino,

-   (2) mono-, di-, and tri-substituted phenyl wherein the substituents    are independently selected from:    -   (i) halo, trifluoromethyl, substituted C₁₋₆ alkyl,    -   (ii) C₁₋₆ alkyloxy, substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy,        substituted C₃₋₆ alkenyloxy,    -   (iii) C₁₋₆ alkyl-amino, di(C₁₋₆ alkyl)amino, substituted C₁₋₆        alkyl-amino, di(substituted C₁₋₆ alkyl)amino, C₃₋₆        alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆        alkenyl-amino, di(substituted C₃₋₆ alkenyl)amino, or    -   (iv) pyrrolidino, piperidino, morpholino, imidazolyl,        substituted imidazolyl, piperazino, 4-N—C₁₋₄ alkylpiperazino,        4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆        alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino,        4-N—(C₁₋₆ alkylamino C₁₋₄ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino        C₃₋₆ alkenyl)piperazino,        wherein the substituents are selected from the group consisting        of:    -   (a) hydrogen, hydroxy, halo, trifluoromethyl,    -   (b) C₁₋₆ alkylalkoxy, C₁₋₆ alkylamino, C₁₋₆ alkylthio,    -   (c) C₃₋₆ alkenyloxy, C₃₋₆ alkenylamino, C₃₋₆ alkenylthio, or    -   (d) pyrrolidino, piperidino, morpholino, imidazolyl, substituted        imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆        alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino,        4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino        C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆        alkenyl)piperazino;        with the proviso that at least one of R₂ and R₃ group be        selected from [B (2)] and the phenyl and the substituents be        selected from (ii)-(v) above; or R₂ and R₃ taken together        forming an aryl group such as phenyl, pyridyl, in which the aryl        may be optionally substituted, wherein the substituents are        defined as above in (i)-(iv);        and R₄ is selected from the group consisting of:    -   (a) hydrogen;    -   (b) substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the        substituents are independently selected from the group        consisting of:        -   (i) hydrogen, hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio, C₁₋₆            alkylamino, phenyl-C₁₋₆ alkylamino, C₁₋₆ alkoxycarbonyl;        -   (ii) substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy, substituted            C₃₋₆ alkenyloxy,        -   (iii) di(C₁₋₆ alkyl)amino, substituted C₁₋₆ alkyl-amino,            di(substituted C₁₋₆ alkyl)amino, C₃₋₆ alkenyl-amino, di(C₃₋₆            alkenyl)amino, substituted C₃₋₆ alkenyl-amino,            di(substituted C₃₋₆ alkenyl)amino; and        -   (iv) pyrrolidino, piperidino, morpholino, imidazolyl,            substituted imidazolyl, piperazino, 4-N—C₁₋₆            alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆            alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆            alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆            alkyl)piperazino, and 4-N—(C₁₋₆ alkylamino C₃₋₆            alkenyl)piperazino; and    -   (c) aryl C₀₋₁₁ alkyl wherein the aryl group is selected from        phenyl, imidazolyl, furyl, thienyl.

In some embodiments, the invention provides a compound of Formula 1a, inthe form of a free compound or its pharmaceutically acceptable pro-drug,metabolite, analogue, derivative, solvate or salt, for use in themethods of the invention, wherein:

wherein the substituents R₁, R₂, R₃, and R₄ are defined as in A or B:

-   -   (A) R₁ is selected from the group consisting of:    -   (i) substituted C₁₋₁₁, alkyl or substituted C₂₋₁₁ alkenyl,        wherein the substituents are selected from the group consisting        of hydroxy and C₁₋₆ alkyloxy; and    -   (ii) mono-, di-, or tri-substituted aryl-C₀₋₁₁ alkyl wherein        aryl is selected from the group consisting of phenyl, furyl, and        thienyl wherein the substituents are selected from the group        consisting of:        -   (a) phenyl, trans-2-phenylethenyl, 2-phenylethynyl, or            2-phenylethyl, wherein the phenyl group is mono- or            disubstituted wherein the substituents are selected from the            group consisting of hydroxy, halo, C₁₋₄ alkyl and C₁₋₄            alkyloxy;        -   (b) substituted C₁₋₆ alkyl, substituted C₂₋₆ alkyloxy,            substituted C₂₋₆ alkylthio, or substituted C₂₋₆            alkoxycarbonyl, wherein the substituents are selected from            the group consisting of C₁₋₆ alkoxy, and C₁₋₆ alkylthio; and        -   (c) C₁₋₁₁CO₂R₅, C₁₋₁₁CONHR₅, trans-CH═CHCO₂R₅, or            trans-CH═CHCONHR₅ wherein R₅ is C₁₋₁₁ alkyl, phenyl C₁₋₁₁            alkyl, or C₁₋₆ alkoxycarbonylmethyleneoxy;

R₂ and R₃ are each independently selected from the group consisting ofmono-, di, and tri-substituted phenyl wherein the substituents areindependently selected from:

-   -   (i) substituted C₁₋₆ alkyl;    -   (ii) substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy, or substituted        C₃₋₆ alkenyloxy;    -   (iii) substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆        alkyl)amino;    -   (iv) C₃₋₆ alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆        alkenyl-amino, or di(substituted C₃₋₆ alkenyl)amino; and    -   (v) pyrrolidino, piperidino, morpholino, imidazolyl, substituted        imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆        alkenylpiperazino, 4-N— (C₁₋₆ alkoxy-C₁₋₆alkyl)piperazino,        4-N—(C₁₋₆ alkoxy-C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆        alkylamino-C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆        alkylamino-C₃₋₆alkenyl)piperazino;

wherein the substituents for (i), (ii), (iii), and (iv) are selectedfrom the group consisting of:

-   -   (a) hydroxy, C₁₋₆ alkoxy, or C₁₋₆ alkylamino;    -   (b) C₃₋₆ alkenyloxy, or C₃₋₆ alkenylamino; and    -   (c) pyrrolidino, piperidino, morpholino, imidazolyl, substituted        imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆        alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino,        4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆        alkylamino-C₁₋₄ alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆        alkenyl)piperazino;

or R₂ and R₃ are taken together to form an aryl group or substitutedaryl, wherein the substituents are defined as above in (i)-(iv);

and R₄ is selected from the group consisting of:

-   -   (i) hydrogen;    -   (ii) substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the        substituents are independently selected from the group        consisting of hydrogen, hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio,        C₁₋₆ alkylamino, phenyl-C₁₋₆ alkylamino, and C₁₋₆        alkoxycarbonyl; and    -   (iii) substituted aryl C₀₋₁₁ alkyl wherein the aryl group is        selected from phenyl, imidazolyl, furyl, and thienyl in which        the substituents are selected from the group consisting of:        -   (a) hydroxy, C₁₋₆ alkoxy, or C₁₋₆ alkylamino;        -   (b) C₃₋₆ alkenyloxy, or C₃₋₆ alkenylamino; and        -   (c) pyrrolidino, piperidino, morpholino, imidazolyl,            substituted imidazolyl, piperazino, 4-N—C₁₋₆            alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆            alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆            alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆            alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆            alkenyl)piperazino; or

(B) R₁ is selected from the group consisting of:

-   -   mono-, di-, and tri-substituted aryl-C₀₋₆ alkyl wherein aryl is        selected from the group consisting of phenyl and thienyl, and        the substituents are selected from the group consisting of:    -   (i) trans-2-substituted benzimidazolylethenyl,        trans-2-substituted benzoxazolylethenyl, or trans-2-substituted        benzthiazolylethenyl, in which the substituents are selected        from the group consisting of hydrogen, hydroxy, halo,        trihalomethyl, C₄ alkyl, C₁₋₄ alkyloxy, C₁₋₄ alkyloxycarbonyl,        C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₃₋₆ alkenylamino, di(C₃₋₆        alkenyl)amino, C₁₋₄ alkyloxy-C₁₋₄ alkylamino, substituted C₁₋₄        alkyl, substituted C₁₋₄ alkyloxy, substituted C₁₋₄        alkyloxycarbonyl, substituted C₁₋₄ alkylamino, di(substituted        C₁₋₄ alkyl)amino, substituted C₃₋₆ alkenylamino, and        di(substituted C₃₋₆ alkenyl)amino, wherein the substituents are        selected from the group consisting of:        -   (a) hydroxy, C₁₋₆ alkoxy, or C₁₋₄ alkylamino;        -   (b) C₃₋₆ alkenyloxy, or C₃₋₆ alkenylamino; and        -   (c) pyrrolidino, piperidino, morpholino, imidazolyl,            substituted imidazolyl, piperazino, 4-N—C₁₋₆            alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆            alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆            alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆            alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆            alkenyl)piperazino;    -   (ii) trans-2-cyano ethenyl, trans-2-alkylsulfonyl ethenyl,        trans-2-alkenylsulfonyl ethenyl, trans-2-substituted        alkylsulfonyl ethenyl, and trans-2-substituted alkenylsulfonyl        ethenyl, wherein the substituents are selected from the group        consisting of:        -   (a) hydroxy, C₁₋₆ alkoxy, or C₁₋₆ alkylamino;        -   (b) C₃₋₆ alkenyloxy, or C₃₋₆ alkenylamino; and        -   (c) pyrrolidino, piperidino, morpholino, imidazolyl,            substituted imidazolyl, piperazino, 4-N—C₁₋₆            alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₄            alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆            alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆            alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆            alkenyl)piperazino;    -   (iii) C₁₋₆ CO₂R₅, trans-CH═CHCO₂R₅, C₁₋₆CONHR₅, or        trans-CH═CHCONHR₅, wherein R₅ is C₁₋₆ alkoxy-C₂₋₆ alkyl,        amino-C₂₋₆ alkyl, C₁₋₆ alkylamino-C₂₋₆ alkyl, di(C₁₋₆        alkyl)amino-C₂₋₆ alkyl, C₁₋₆ alkylthio-C₂₋₆ alkyl, substituted        C₁₋₆ alkoxy-C₂₋₆ alkyl, substituted C₁₋₆ alkylamino-C₂₋₆ alkyl,        di(substituted C₁₋₆ alkyl)amino-C₂₋₆ alkyl, or substituted C₁₋₆        alkylthio-C₂₋₆ alkyl, in which the substituents are selected        from the group consisting of pyrrolidino, piperidino morpholino,        piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆        alkenylpiperazino, 4-N—(C₁₋₆ alkoxy-C₁₋₆ alkyl)piperazino,        4-N—(C₁₋₆ alkoxy-C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆        alkylamino-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆        alkenyl)piperazino, imidazolyl, oxazolyl, and thiazolyl;    -   (iv) C₁₋₆ CONHR₅, or trans-CH═CHCONR₆R₇, wherein R₆ and R₇ are        independently selected from the group consisting of C₁₋₆ alkyl,        phenyl-C₁₋₆ alkyl, C₁₋₆ alkoxycarbonylmethyleneoxy, hydroxy-C₂₋₆        alkyl, C₁₋₆ alkyloxy-C₂₋₆ alkyl, amino-C₂₋₆ alkyl, C₁₋₆        alkylamino-C₂₋₆ alkyl, di(C₁₋₆ alkyl)amino-C₂₋₆ alkyl, C₁₋₆        alkylthio-C₇₋₆ alkyl, substituted C₁₋₆ alkoxy-C₂₋₆ alkyl,        substituted C₁₋₆ alkylamino-C₂₋₆ alkyl, di(substituted C₁₋₆        alkyl)amino-C₂₋₆ alkyl, substituted C₁₋₆ alkylthio-C₂₋₆ alkyl,        wherein the substituents are selected from the group consisting        of pyrrolidino, piperidino, morpholino, piperazino, 4-N—C₁₋₆        alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy        C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy-C₃₋₆ alkenyl)piperazino,        4-N—(C₁₋₆ alkylamino-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆        alkylamino-C₃₋₆ alkenyl)piperazino, imidazolyl, oxazolyl, and        thiazolyl;    -   (v) R₇—C(O)—C₁₋₆ alkyl or R₇—C(O)—C₂₋₆ alkenyl, in which R₇ is        defined as above in [B(iv)];    -   (vi) HO—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇—O—C₁₋₄ alkyl-C₂₋₆ alkenyl,        R₇NH—C₃₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl,        R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C(O)—O—C₁₋₆        alkyl-C₂₋₆ alkenyl, R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, or        R₇—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, wherein R₆ and R₇ is defined        as above in [B(iv)]; and    -   (vii) R₇—O—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl, R₇NH—C₀₋₃ alkyl-C₃₋₆        cycloalk-1-yl, R₆R₇N—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl,        R₇NH—C(O)—O—C₀₋₃ C₃₋₆ cycloalk-1-yl, R₆R₇N—C(O)—O—C₀₋₃        alkyl-C₃₋₆ cycloalk-1-yl, R₇O—C(O)—O—C₀₋₃ alkyl-C₃₋₆        cycloalk-1-yl, R₇—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl,        R₇₀—C(O)—Co-3 alkyl-C₃₋₆ cycloalk-1-yl, wherein R₇ and R₆ are        defined as above in [B(iv)];

R₂ and R₃ are each independently selected from the group consisting of:

-   -   (viii) hydrogen, halo, trihatomethyl, C₁, alkyl, substituted        C₁₋₆ alkyl, C₂₋₆ alkenyl, substituted C₂₋₆ alkenyl, C₁₋₆        alkyloxy, substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy,        substituted C₃₋₆ alkenyloxy, C₁₋₆ alkylamino, substituted C₁₋₆        alkylamino, C₃₋₆ alkenylamino, or substituted C₃₋₆ alkenylamino;        and    -   (ix) mono-, di-, or tri-substituted phenyl wherein the        substituents are independently selected from the group        consisting of:    -   (a) halo, trifluoromethyl, or substituted C₁₋₆ alkyl;    -   (b) C₁₋₆ alkyloxy, substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy,        substituted C₃₋₆ alkenyloxy;    -   (c) C₁₋₆ alkyl-amino, di(C₁₋₆ alkyl)amino, substituted C₁₋₆        alkyl-amino, di(substituted C₁₋₆ alkyl)amino, C₃₋₆        alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆        alkenyl-amino, or di(substituted C₃₋₆ alkenyl)amino; and    -   (d) pyrrolidino, piperidino, morpholino, imidazolyl, substituted        imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆        alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino,        4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino        C₁₋₆ alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆        alkenyl)piperazino;        wherein the substituents for (a), (b), (c), and (d) are selected        from the group consisting of:    -   (1) hydrogen, hydroxy, halo, or trifluoromethyl;    -   (2) C₁₋₆ alkylalkoxy, C₁₋₆ alkylamino, or C₁₋₆ alkylthio;    -   (3) C₃₋₆ alkenyloxy, C₃₋₆ alkenylamino, or C₃₋₆ alkenylthio; and    -   (4) pyrrolidino, piperidino, morpholino, imidazolyl, substituted        imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆        alkenylpiperazino, 4-N—(C₁₋₄ alkoxy C₁₋₆ alkyl)piperazino,        4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino        C₁₋₆ alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆        alkenyl)piperazino;

with the proviso that a) at least one of R₂ and R₃ is selected from [B(ix)] and wherein the substituents are selected from [B (ix) (b)-(d)]above; or b) R₂ and R₃ are taken together to form an optionallysubstituted aryl group, wherein the substituents are defined as above in[B (ix) (a)-(d)];

and R₄ is selected from the group consisting of:

-   -   (i) hydrogen;    -   (ii) substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the        substituents are independently selected from the group        consisting of:        -   (a) hydrogen, hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio, C₁₋₆            alkylamino, phenyl-C₁₋₆ alkylamino, or C₁₋₆ alkoxycarbonyl;        -   (b) substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy, or            substituted C₃₋₆ alkenyloxy;        -   (c) di(C₁₋₆ alkyl)amino, substituted C₁₋₆ alkyl-amino,            di(substituted C₁₋₆ alkyl)amino, C₃₋₆ alkenyl-amino, di(C₃₋₆            alkenyl)amino, substituted C₃₋₆ alkenyl-amino, or            di(substituted C₃₋₆ alkenyl)amino; and        -   (d) pyrrolidino, piperidino, morpholino, imidazolyl,            substituted imidazolyl, piperazino, 4-N—C₁₋₄            alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆            alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆            alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆            alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆            alkenyl)piperazino; and        -   (iii) aryl C₀₋₁₁ alkyl wherein the aryl group is selected            from phenyl, imidazolyl, furyl, or thienyl.

In some embodiments of the invention, the compound of Formula 1a is acompound wherein R₁ is selected from the group consisting of mono-, di-,and tri-substituted aryl-C₀₋₆ alkyl wherein aryl is selected from thegroup consisting of phenyl and thienyl, and the substituents areselected from the group consisting of:

-   -   (a) C₁₋₆ CO₂R₅, trans-CH═CHCO₂R₅, C₁₋₆CONHR₅, or        trans-CH═CHCONHR₅;    -   (b) C₁₋₆CONR₆R₇, or trans-CH═CHCONR₆R₇;    -   (c) R₇ C(O) C₁₋₆ alkyl or R₇ C(O)C₂₋₆ alkenyl; and    -   (d) HO—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇—O—C₁₋₆ alkyl-C₂₋₆ alkenyl,        R₇NH—C₁₋₄ alkyl-C₂₋₆ alkenyl, R₆R₇N—C₁₋₄ alkyl-C₂₋₆ alkenyl,        R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C(O)—O—C₁₋₆        alkyl-C₂₋₆ alkenyl, R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, or        R₇—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl.

In other embodiments, the compound of Formula 1a is a compound whereinR₁ is selected from the group consisting of mono-, di-, andtri-substituted aryl-C₀₋₆ alkyl wherein aryl is selected from the groupconsisting of phenyl and thienyl, and the substituents are selected fromthe group consisting of:

-   -   (a) C₁₋₆ CO₂R₅, trans-CH═CHCO₂R₅, C₁₋₆CONHR₅, or        trans-CH═CHCONHR₅;    -   (b) C₁₋₆CONR₆R₇, or trans-CH═CHCONR₆R₇;    -   (c) R₇ C(O)C₁₋₆ alkyl or R₇ C(O)C₂₋₆ alkenyl; and    -   (d) HO—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇—O—C₁₋₆ alkyl-C₂₋₆ alkenyl,        R₇NH—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl,        R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇N—C(O)—O—C₁₋₆ alkyl-C₂₋₆        alkenyl, R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, or R₇—C(O)—O—C₁₋₆        alkyl-C₂₋₆ alkenyl.

In various embodiments of the invention, the compound of Formula 1a is acompound wherein R₁ is selected from the group consisting of mono-, di-,and tri-substituted aryl-C₀₋₆ alkyl wherein aryl is selected from thegroup consisting of phenyl and thienyl, and the substituents are HO—C₁₋₆alkyl-C₂₋₆ alkenyl, R₇—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH—C₁₋₆ alkyl-C₂₋₆alkenyl, R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆alkenyl, R₆R₇N—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇O—C(O)—O—C₁₋₆alkyl-C₂₋₆ alkenyl, or R₇—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl.

In other embodiments, R₁ is selected from the group consisting of mono-,di-, and tri-substituted aryl-C₀₋₆ alkyl wherein the aryl-C₀₋₆ alkyl isphenyl-C₀₋₆ alkyl. In some embodiments, R₁ is selected from the groupconsisting of mono-, di-, and tri-substituted aryl-C₀₋₆ alkyl whereinthe aryl-CO₀₋₆ alkyl is aryl-C₀alkyl, which is aryl with no alkyl groupattached directly to aryl.

In various embodiments, R₂ and R₃ are each independently selected fromthe group consisting of: mono-, di-, and tri-substituted phenyl whereinthe substituents are independently selected from the group consistingof:

-   -   (i) C₁₋₆ alkyloxy, substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy,        or substituted C₃₋₆ alkenyloxy;    -   (ii) C₁₋₆ alkyl-amino, di(C₁₋₆ alkyl)amino, substituted C₁₋₆        alkyl-amino, di(substituted C₁₋₆ alkyl)amino, C₃₋₆        alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆        alkenyl-amino, or di(substituted C₃₋₆ alkenyl)amino, and    -   (iii) pyrrolidino, piperidino, morpholino, imidazolyl,        substituted imidazolyl, piperazino, 4-N—C₁₋₄ alkylpiperazino,        4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆        alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino,        4-N—(C₁₋₆ alkylamino C₁₋₆ alkyl)piperazino, or 4-N—(C₁₋₆        alkylamino C₃₋₆ alkenyl)piperazino.

In some embodiments, R₂ and R₃ are each independently selected from thegroup consisting of: mono-, di-, and tri-substituted phenyl wherein thesubstituents are independently selected from the group consisting ofC₁₋₆ alkyl-amino, di(C₁₋₆ alkyl)amino, substituted C₁₋₆ alkyl-amino,di(substituted C₁₋₆ alkyl)amino, C₃₋₆ alkenyl-amino, di(C₃₋₆alkenyl)amino, substituted C₃₋₆ alkenyl-amino, and di(substituted C₃₋₆alkenyl)amino. In some embodiments, R₄ is hydrogen.

In some embodiments, the compound of Formula 1a is a compound of Formula1b:

wherein each instance of R_(a) is independently C₁₋₆ alkyl-amino,di(C₁₋₆ alkyl)amino, substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆alkyl)amino, C₃₋₆ alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆alkenyl-amino, or di(substituted C₃₋₆ alkenyl)amino; and

R_(b) is HO—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇—O—C₁₋₆alkyl-C₂₋₆ alkenyl,R₇NH—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C(O)—O—C₁₋₆ alkyl-C₂₋₆alkenyl, R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, or R₇—C(O)—O—C₁₋₆;alkyl-C₂₋₆ alkenyl.

In preferred embodiments, the compound is of Formula 2:

in the form of a free compound or as its pharmaceutically-acceptablepro-drug, metabolite, analogue, derivative, solvate or salt.

In some aspects of the present invention, the compound of Formula 1 or1a (such as Formula 1b or 2) is adminstered to a subject suffering froma lysosomal storage disease. The lysosomal storage disease may becharacterized by a defect in glycosphingolipid synthesis. In someembodiments, the defect is in neutral glycosphingolipid synthesis. Inother embodiments, the disease is characterized by a defect in ceramidesynthesis. The disease may be Gaucher's disease or Fabry's disease. Insome embodiments, the lysosomal storage disease may be characterized bya defect in ganglioside synthesis in the subject, wherein theganglioside is a GM1 or GM2 ganglioside. The disease may be Tay Sach'sdisease, Sandhoff's disease, or cystic fibrosis.

In another aspect of the present invention, a method for treating alipid storage disease in a subject comprising administering to thesubject an effective amount of: a first compound of Formula 1 or 1a(such as Formula 1b or 2) and a second compound effective to treat thelipid storage disease, is provided. In some embodiments, the secondcompound is a glucosylceramide synthase inhibitor. In preferredembodiments, the glucosylceramide synthase inhibitor is miglustat. Inother embodiments, the second compound is an enzyme administered asenzyme replacement therapy or a pharmacological chaperone which binds tothe enzyme and promotes trafficking of the enzyme from the endoplasmicreticulum to the lysosome.

In yet another aspect, the present invention provides a method fortreating a subject having a condition associated with verotoxin, choleratoxin, or uropathic E. Coli comprising administering an effective amountof a composition of a compound of Formula 1 or 1a (such as Formula 1b or2) to a subject in need thereof.

The present invention further provides compositions comprising aglucosylceramide synthase inhibitor and compound of Formula 1 or 1a(such as Formula 1b or 2). In some embodiments, the glucosylceramidesynthase inhibitor is miglustat.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the disclosure are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 depicts the glucosylceramide pathway.

FIG. 2 depicts decrease of longer chain GSL formation after treatmentwith compositions of the present invention.

FIG. 3 shows the effect of a compound of Formula 2 on Gb3 accumulationin the Fabry mouse model liver tissue.

FIG. 4 shows the effect of a compound of Formula 2 on Gb3 accumulationin the Fabry mouse model heart tissue.

DETAILED DESCRIPTION

The present invention describes methods of modulating GSL levels using aclass of substituted imidazole derivatives or compounds. The compoundsare useful in modulating GSL accumulation, for example complex GSLs,such as neutral GSLs. In another aspect, the compounds are useful inmodulating a subset of GSLs, such as neutral GSLs (for example, GlcCer,LacCer, Gb3, Gb4) or acidic GSLs, such as gangliosides. Such compoundsare useful for treating conditions involving abnormal glycolipidsynthesis or metabolism, for example resulting in accumulation of a GSL.

I. Compounds Useful for Modulating GSL Levels

The class of imidazole derivatives or compounds is as depicted inFormula 1:

in the form of a free compound or its pharmaceutically acceptablepro-drug, metabolite, analogue, derivative, solvate or salt wherein thesubstituents R₁, R₂, R₃, and R₄ are defined as described in (a) and (b)below:

(a) when R₁ is selected from the group consisting of:

(i) substituted C₁₋₁₁ alkyl or substituted C₂₋₁₁ alkenyl, wherein thesubstituents are selected from the group consisting of hydroxy, C₁₋₆alkyloxy; or

(ii) mono-, di-, and tri-substituted aryl-C₀₋₁₁ alkyl wherein aryl isselected from the group consisting of phenyl, furyl, thienyl wherein thesubstituents are selected from the group consisting of:

-   -   (a) phenyl, trans-2-phenylethenyl, 2-phenylethynyl,        2-phenylethyl, wherein the said phenyl group is mono- or        disubstituted with a member selected from the group consisting        of hydroxy, halo, C₁₋₄ alkyl and C₁₋₄ alkyloxy,    -   (b) substituted C₁₋₆ alkyl, substituted C₂₋₆ alkyloxy,        substituted C₂₋₆ alkylthio, substituted C₂₋₆ alkoxycarbonyl,        wherein the substituents are selected from the group consisting        of C₁₋₆ alkoxy, and C₁₋₆ alkylthio; and    -   (c) C₁₋₁₁ CO₂R₅, C₁₋₁₁CONHR₅, trans-CH═CHCO₂R₅, or        trans-CH═CHCONHR₅ wherein R₅ is C₁₋₁₁ alkyl, or phenyl C₁₋₁₁        alkyl, C₁₋₆ alkoxycarbonylmethyleneoxy;

then R₂ and R₃ are each independently selected from the group consistingof mono-, di, and tri-substituted phenyl wherein the substituents areindependently selected from:

-   -   (i) substituted C₁₋₆ alkyl,    -   (ii) substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy, substituted        C₃₋₆ alkenyloxy,    -   (iii) substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆        alkyl)amino,    -   (iv) C₃₋₆ alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆        alkenyl-amino, di(substituted C₃₋₆ alkenyl)amino,    -   (v) pyrrolidino, piperidino, morpholino, imidazolyl, substituted        imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆        alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino,        4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁, alkylamino        C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆        alkenyl)piperazino,    -   wherein the substituents are selected from the group consisting        of:        -   (a) hydroxy, C₁₋₆ alkylalkoxy, C₁₋₆ alkylamino        -   (b) C₃₋₆ alkenyloxy, C3-6 alkenylamino, or        -   (c) pyrrolidino, piperidino, morpholino, imidazolyl,            substituted imidazolyl, piperazino, 4-N—C₁₋₆            alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₄            alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆            alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆            alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆            alkenyl)piperazino,

or R₂ and R₃ taken together forming an aryl group or substituted aryl,wherein the substituents are defined as above in (i)-(v);

and R₄ is selected from the group consisting of:

-   -   (i) hydrogen;    -   (ii) substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the        substituents are independently selected from the group        consisting of hydrogen, hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio,        C₁₋₆ alkylamino, phenyl-C₁₋₆ alkylamino, C₁₋₆ alkoxycarbonyl; or    -   (iii) substituted aryl C₀₋₁₁ alkyl wherein the aryl group is        selected from phenyl, imidazolyl, furyl, thienyl in which the        substituents are selected from A(a-c); or

(b) when R₁ is selected from the group consisting of:

Mono-, di-, and tri-substituted aryl-C₀₋₆ alkyl wherein aryl is selectedfrom the group consisting of phenyl, thienyl, and the substituents areselected from the group consisting of:

-   -   (a) trans-2-substituted benzimidazolylethenyl,        trans-2-substituted benzoxazolylethenyl, trans-2-substituted        benzthiazolylethenyl, in which the substituents are selected        from the group consisting of hydrogen, hydroxy, halo,        trihalomethyl, C₁₋₄ alkyl and C₁₋₄ alkyloxy, C₁₋₄        alkyloxycarbonyl, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₃₋₆        alkenylamino, di(C₃₋₆ alkenyl)amino, C₁₋₄ alkyloxy-C₁₋₄        alkylamino, substituted C₁₋₄ alkyl and C₁₋₄ alkyloxy,        substituted C₁₋₄ alkyloxycarbonyl, substituted C₁₋₄ alkylamino,        di(substituted C₁₋₄ alkyl)amino, substituted C₃₋₆ alkenylamino,        di(substituted C₃₋₆ alkenyl)amino, wherein the substituents are        as defined above,    -   (b) trans-2-cyano ethenyl, trans-2-alkylsulfonyl ethenyl,        trans-2-alkenylsulfonyl ethenyl, trans-2-substituted        alkylsulfonyl ethenyl, trans-2-substituted alkenylsulfonyl        ethenyl, in which the substituents are defined above,    -   (c) C₁₋₆ CO₂R₅, trans-CH═CHCO₂R₅, C₁₋₆CONHR₅, or        trans-CH—CHCONHR₅, wherein R₅ is C₁₋₆ alkoxy C₂₋₆ alkyl, amino        C₂₋₆ alkyl, C₁₋₆ alkylamino C₂₋₆ alkyl, di(C₁₋₆ alkyl)amino C₂₋₆        alkyl, C₁₋₆ alkylthio C₂₋₆ alkyl, substituted C₁₋₆ alkoxy C₂₋₆        alkyl, substituted C₁₋₆ alkylamino C₂₋₆ alkyl, di(substituted        C₁₋₆ alkyl)amino C₂₋₆ alkyl, substituted C₁₋₆ alkylthio C₂₋₆        alkyl, in which the substituents are selected from the group        consisting of pyrrolidino, piperidino morpholino, piperazino,        4-N—C₁₋₄ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆        alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆        alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆ alkyl)piperazino,        4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino, imidazolyl,        oxazolyl, thiazolyl,    -   (d) C₁₋₆CONR₆R₇, or trans-CH═CHCONR₆R₇, wherein R₆ and R₇ are        independently selected from the group consisting of C₁₋₆ alkyl,        phenyl C₁₋₆ alkyl, C₁₋₆ alkoxycarbonylmethyleneoxy, hydroxy C₂₋₆        alkyl, C₁₋₆ alkyloxy C₂₋₆ alkyl, amino C₂₋₆ alkyl, C₁₋₆        alkylamino C₂₋₆ alkyl, di(C₁₋₆ alkyl)amino C₂₋₆ alkyl, C₁₋₆        alkylthio C₂₋₆ alkyl, substituted C₁₋₆ alkoxy C₂₋₆ alkyl,        substituted C₁₋₆ alkylamino C₂₋₆ alkyl, di(substituted C₁₋₆        alkyl)amino C₂₋₆ alkyl, substituted C₁₋₆ alkylthio C₂₋₆ alkyl,        wherein the substituents are selected from the group consisting        of pyrrolidino, piperidino, morpholino, piperazino, 4-N—C₁₋₆        alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy        C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino,        4-N—(C₁₋₆ alkylamino C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino        C₃₋₆ alkenyl)piperazino, imidazolyl, oxazolyl, thiazolyl,    -   (e) R₇ C(O) C₁₋₆ alkyl, R₇ C(O)C₂₋₆ alkenyl, in which R₇ is        defined as above [2(d)],    -   (f) HO—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇—O—C₁₋₆ alkyl-C₂₋₆ alkenyl,        R₇NH—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl,        R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₄ alkenyl, R₆R₇N—C(O)—O—C₁₋₆        alkyl-C₂₋₆ alkenyl, R₇O—C(O)—O—C₁₋₄ alkyl-C₂₋₄ alkenyl,        R₇—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, wherein R₆ and R₇ is defined        as above [2(d)],    -   (g) R₇—O—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl, R₇NH—C₀₋₃ alkyl-C₃₋₆        cycloalkan-1-yl, R₆R₇N—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl,        R₇NH—C(O)—O—C₀₋₃ C₃₋₆ cycloalkan-1-yl, R₆R₇N—C(O)—O—C₀₋₃        alkyl-C₃₋₆ cycloalkan-1-yl, R₇O—C(O)—O—C₀₋₃ alkyl-C₃₋₆        cycloalkan-1-yl, R₇—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl,        R₇O—C(O)—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl, wherein R₇ and is        defined as above [B(d)];

then R₂ and R₃ are each independently selected from the group consistingof:

-   (1) hydrogen, halo, trihalomethyl, C₁₋₆ alkyl, substituted C₁₋₆    alkyl, C₂₋₆ alkenyl, substituted C₁₋₆ alkenyl, C₁₋₆ alkyloxy,    substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy, substituted C₃₋₆    alkenyloxy, C₁₋₆ alkylamino, substituted C₁₋₆ alkylamino, C₃₋₆    alkenylamino, substituted C₃₋₆ alkenylamino,-   (2) mono-, di-, and tri-substituted phenyl wherein the substituents    are independently selected from:    -   (i) halo, trifluoromethyl, substituted CO₄ alkyl,    -   (ii) C₁₋₆ alkyloxy, substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy,        substituted CO₃₋₆ alkenyloxy,    -   (iii) C₁₋₆ alkyl-amino, di(C₁₋₆ alkyl)amino, substituted C₁₋₆        alkyl-amino, di(substituted C₁₋₆ alkyl)amino, C₃₋₆        alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆        alkenyl-amino, di(substituted C₃₋₆ alkenyl)amino, or    -   (iv) pyrrolidino, piperidino, morpholino, imidazolyl,        substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino,        4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₄ alkoxy C₁₋₆        alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino,        4-N—(C₁₋₆ alkylamino C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₄ alkylamino        C₃₋₆ alkenyl)piperazino,        wherein the substituents are selected from the group consisting        of:    -   (a) hydrogen, hydroxy, halo, trifluoromethyl,    -   (b) C₁₋₆ alkylalkoxy, C₁₋₆ alkylamino, C₁₋₆ alkylthio,    -   (c) C₃₋₆ alkenyloxy, C₃₋₆ alkenylamino, C₃₋₆ alkenylthio, or    -   (d) pyrrolidino, piperidino, morpholino, imidazolyl, substituted        imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆        alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino,        4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino        C₁₋₄ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆        alkenyl)piperazino;

with the proviso that at least one of R₂ and R₃ group be selected from[B (2)] and the phenyl and the substituents be selected from (ii)-(v)above; or R₂ and R₃ taken together forming an aryl group such as phenyl,pyridyl, in which the aryl may be optionally substituted, wherein thesubstituents are defined as above in (i)-(iv);

and R₄ is selected from the group consisting of:

-   -   (a) hydrogen;    -   (b) substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the        substituents are independently selected from the group        consisting of:        -   (i) hydrogen, hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio, C₁₋₆            alkylamino, phenyl-C₁₋₆ alkylamino, C₁₋₆ alkoxycarbonyl;        -   (ii) substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy, substituted            C₃₋₆ alkenyloxy,        -   (iii) di(C₁₋₆ alkyl)amino, substituted C₁₋₆ alkyl-amino,            di(substituted C₁₋₆ alkyl)amino, C₃₋₆ alkenyl-amino, di(C₃₋₆            alkenyl)amino, substituted C₃₋₆ alkenyl-amino,            di(substituted C₃₋₆ alkenyl)amino; and        -   (iv) pyrrolidino, piperidino, morpholino, imidazolyl,            substituted imidazolyl, piperazino, 4-N—C₁₋₆            alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆            alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆            alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆            alkyl)piperazino, and 4-N—(C₁₋₆ alkylamino C₃₋₆            alkenyl)piperazino; and    -   (d) aryl C₀₋₁₁ alkyl wherein the aryl group is selected from        phenyl, imidazolyl, furyl, thienyl.

In some embodiments, the invention provides a compound of Formula 1a, inthe form of a free compound or its pharmaceutically acceptable pro-drug,metabolite, analogue, derivative, solvate or salt, for use in themethods of the invention, wherein:

wherein the substituents R₁, R₂, R₃, and R₄ are defined as in A or B:

-   -   (B) R₁ is selected from the group consisting of:    -   (i) substituted C₁₋₁₁ alkyl or substituted C₂₋₁₁ alkenyl,        wherein the substituents are selected from the group consisting        of hydroxy and C₁₋₆ alkyloxy; and    -   (ii) mono-, di-, or tri-substituted aryl-C₀₋₁₁ alkyl wherein        aryl is selected from the group consisting of phenyl, furyl, and        thienyl wherein the substituents are selected from the group        consisting of:    -   (a) phenyl, trans-2-phenylethenyl, 2-phenylethynyl, or        2-phenylethyl, wherein the phenyl group is mono- or        disubstituted wherein the substituents are selected from the        group consisting of hydroxy, halo, C₁₋₄ alkyl and C₁₋₄ alkyloxy;    -   (b) substituted C₁₋₆ alkyl, substituted C₂₋₆ alkyloxy,        substituted C₂₋₆ alkylthio, or substituted C₂₋₆ alkoxycarbonyl,        wherein the substituents are selected from the group consisting        of C₁₋₆ alkoxy, and C₁₋₆ alkylthio; and    -   (c) C₁₋₁₁ CO₂R₅, C₁₋₁₁CONHR₅, trans-CH═CHCO₂R₅, or        trans-CH═CHCONHR₅ wherein R₅ is C₁₋₁₁ alkyl, phenyl C₁₋₁₁ alkyl,        or C₁₋₆ alkoxycarbonylmethyleneoxy;

R₂ and R₃ are each independently selected from the group consisting ofmono-, di, and tri-substituted phenyl wherein the substituents areindependently selected from;

-   -   (i) substituted C₁₋₆ alkyl;    -   (ii) substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy, or substituted        C₃₋₆ alkenyloxy;    -   (iii) substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆        alkyl)amino;    -   (iv) C₃₋₆ alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆        alkenyl-amino, or di(substituted C₃₋₆ alkenyl)amino; and    -   (v) pyrrolidino, piperidino, morpholino, imidazolyl, substituted        imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆        alkenylpiperazino, 4-N—(C₁₋₆ alkoxy-C₁₋₆ alkyl)piperazino,        4-N—(C₁₋₆ alkoxy-C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆        alkylamino-C₁₋₆ alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆        alkenyl)piperazino;

wherein the substituents for (i), (ii), (iii), and (iv) are selectedfrom the group consisting of:

-   -   (a) hydroxy, C₁₋₆ alkoxy, or C₁₋₆ alkylamino;    -   (b) C₃₋₆ alkenyloxy, or C₃₋₆ alkenylamino; and    -   (c) pyrrolidino, piperidino, morpholino, imidazolyl, substituted        imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆        alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino,        4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆        alkylamino-C₁₋₆ alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆        alkenyl)piperazino;

or R₂ and R₃ are taken together to form an aryl group or substitutedaryl, wherein the substituents are defined as above in (i)-(iv);

and R₄ is selected from the group consisting of:

-   -   (i) hydrogen;    -   (ii) substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the        substituents are independently selected from the group        consisting of hydrogen, hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio,        C₁₋₆ alkylamino, phenyl-C₁₋₆ alkylamino, and C₁₋₆        alkoxycarbonyl; and    -   (iii) substituted aryl C₀₋₁₁ alkyl wherein the aryl group is        selected from phenyl, imidazolyl, furyl, and thienyl in which        the substituents are selected from the group consisting of:    -   (a) hydroxy, C₁₋₆ alkoxy, or C₁₋₆ alkylamino;    -   (b) C₃₋₆ alkenyloxy, or C₃₋₆ alkenylamino; and    -   (c) pyrrolidino, piperidino, morpholino, imidazolyl, substituted        imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆        alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino,        4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆        alkylamino-C₁₋₆ alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆        alkenyl)piperazino; or

(B) R₁ is selected from the group consisting of:

-   -   mono-, di-, and ti-substituted aryl-C₀₋₆ alkyl wherein aryl is        selected from the group consisting of phenyl and thienyl, and        the substituents are selected from the group consisting of:    -   (i) trans-2-substituted benzimidazolylethenyl,        trans-2-substituted benzoxazolylethenyl, or trans-2-substituted        benzthiazolylethenyl, in which the substituents are selected        from the group consisting of hydrogen, hydroxy, halo,        trihalomethyl, C₁₋₄ alkyl, C₁₋₄ alkyloxy, C₁₋₄ alkyloxycarbonyl,        C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₃₋₆ alkenylamino, di(C₃₋₆        alkenyl)amino, C₁₋₄ alkyloxy-C₁₋₄ alkylamino, substituted C₁₋₄        alkyl, substituted C₁₋₄ alkyloxy, substituted C₁₋₄        alkyloxycarbonyl, substituted C₁₋₄ alkylamino, di(substituted        C₁₋₄ alkyl)amino, substituted C₃₋₆ alkenylamino, and        di(substituted C₃₋₆ alkenyl)amino, wherein the substituents are        selected from the group consisting of:        -   (a) hydroxy, C₁₋₆ alkoxy, or C₁₋₆ alkylamino;        -   (b) C₃₋₆ alkenyloxy, or C₃₋₆ alkenylamino; and        -   (c) pyrrolidino, piperidino, morpholino, imidazolyl,            substituted imidazolyl, piperazino, 4-N—C₁₋₆            alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆            alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆            alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆            alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆            alkenylpiperazino;    -   (ii) trans-2-cyano ethenyl, trans-2-alkylsulfonyl ethenyl,        trans-2-alkenylsulfonyl ethenyl, trans-2-substituted        alkylsulfonyl ethenyl, and trans-2-substituted alkenylsulfonyl        ethenyl, wherein the substituents are selected from the group        consisting of:        -   (a) hydroxy, C₁₋₆ alkoxy, or C₁₋₆ alkylamino;        -   (b) C₃₋₆ alkenyloxy, or C₃₋₆ alkenylamino; and        -   (c) pyrrolidino, piperidino, morpholino, imidazolyl,            substituted imidazolyl, piperazino, 4-N—C₁₋₆            alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆            alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆            alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆            alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆            alkenyl)piperazino;    -   (iii) C₁₋₆ CO₂R₅, trans-CH═CHCO₂R₅, C₁₋₆CONHR₅, or        trans-CH═CHCONHR₅, wherein R₅ is C₁₋₆ alkoxy-C₂₋₆ alkyl,        amino-C₂₋₄ alkyl, C₁₋₆ alkylamino-C₂₋₆ alkyl, di(C₁₋₆        alkyl)amino-C₂₋₆ alkyl, C₁₋₆ alkylthio-C₂₋₆ alkyl, substituted        C₁₋₆ alkoxy-C₂₋₆ alkyl, substituted C₁₋₆ alkylamino-C₂₋₆ alkyl,        di(substituted C₁₋₆ alkyl)amino-C₂₋₆ alkyl, or substituted C₁₋₆        alkylthio-C₂₋₆ alkyl, in which the substituents are selected        from the group consisting of pyrrolidino, piperidino morpholino,        piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆        alkenylpiperazino, 4-N—(C₁₋₆ alkoxy-C₁₋₆ alkyl)piperazino,        4-N—(C₁₋₆ alkoxy-C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆        alkylamino-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆        alkenyl)piperazino, imidazolyl, oxazolyl, and thiazolyl;    -   (iv) C₁₋₆CONHR₅, or trans-CH═CHCONR₆R₇, wherein R₆ and R₇ are        independently selected from the group consisting of C₁₋₆ alkyl,        phenyl-C₁₋₆ alkyl, C₁₋₆ alkoxycarbonylmethyleneoxy, hydroxy-C₂₋₄        alkyl, C₁₋₆ alkyloxy-C₂₋₆ alkyl, amino-C₂₋₆ alkyl, C₁₋₆        alkylamino-C₂₋₆ alkyl, di(C₁₋₆ alkyl)amino-C₂₋₆ alkyl, C₁₋₆        alkylthio-C₂₋₆ alkyl, substituted C₁₋₆ alkoxy-C₂₋₆ alkyl,        substituted C₁₋₆ alkylamino-C₂₋₆ alkyl, di(substituted C₁₋₆        alkyl)amino-C₂₋₆ alkyl, substituted C₁₋₆ alkylthio-C₂₋₆ alkyl,        wherein the substituents are selected from the group consisting        of pyrrolidino, piperidino, morpholino, piperazino, 4-N—C₁₋₆        alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy        C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy-C₃₋₆ alkenylpiperazino,        4-N—(C₁₋₆ alkylamino-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆        alkylamino-C₃₋₆-alkenyl)piperazino, imidazolyl, oxazolyl, and        thiazolyl;    -   (v) R₇—C(O)—C₁₋₆ alkyl or R₇—C(O)—C₂₋₆ alkenyl, in which R₇ is        defined as above in [B(iv)]    -   (vi) HO—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇—O—C₁₋₆ alkyl-C₂₋₆ alkenyl,        R₇NH—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl,        R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C(O)—O—C₁₋₆        alkyl-C₂₋₆ alkenyl, R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, or        R₇—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, wherein R₆ and R₇ is defined        as above in [B(iv)]; and    -   (vii) R₇—O—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl, R₇NH—C₀₋₃ alkyl-C₃₋₆        cycloalk-1-yl, R₆R₇N—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl,        R₇NH—C(O)—O—C₀₋₃ C₃₋₆ cycloalk-1-yl, R₆R₇N—C(O)—O—C₀₋₃        alkyl-C₃₋₆ cycloalk-1-yl, R₇O—C(O)—O—C₀₋₃ alkyl-C₃₋₆        cycloalk-1-yl, R₇—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl,        R₇O—C(O)—Co-3 alkyl-C₃₋₆ cycloalk-1-yl, wherein R₇ and R₆ are        defined as above in [B(iv)];

R₂ and R₃ are each independently selected from the group consisting of:

-   -   (viii) hydrogen, halo, trihalomethyl, C₁₋₆ alkyl, substituted        C₁₋₆ alkyl, C₂₋₆ alkenyl, substituted C₂₋₆ alkenyl, C₁₋₆        alkyloxy, substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy,        substituted C₃₋₆ alkenyloxy, C₁₋₆ alkylamino, substituted C₁₋₆        alkylamino, C₃₋₆ alkenylamino, or substituted C₃₋₆ alkenylamino;        and    -   (ix) mono-, di-, or tri-substituted phenyl wherein the        substituents are independently selected from the group        consisting of:    -   (a) halo, trifluoromethyl, or substituted C₁₋₆ alkyl;    -   (b) C₁₋₆ alkyloxy, substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy,        substituted C₃₋₆ alkenyloxy;    -   (c) C₁₋₆ alkyl-amino, di(C₁₋₆ alkyl)amino, substituted C₁₋₆        alkyl-amino, di(substituted C₁₋₆ alkyl)amino, C₃₋₆        alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆        alkenyl-amino, or di(substituted C₃₋₆ alkenyl)amino; and    -   (d) pyrrolidino, piperidino, morpholino, imidazolyl, substituted        imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆        alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₁₆ alkyl)piperazino,        4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino        C₁₋₆ alkyl)piperazino, or 4-N—(C₁₋₆-alkylamino C₃₋₆        alkenyl)piperazino;        wherein the substituents for (a), (b), (c), and (d) are selected        from the group consisting of:    -   (1) hydrogen, hydroxy, halo, or trifluoromethyl;    -   (2) C₁₋₆ alkylalkoxy, C₁₋₆ alkylamino, or C₁₋₆ alkylthio;    -   (3) C₃₋₆ alkenyloxy, C₃₋₆ alkenylamino, or C₃₋₆ alkenylthio; and    -   (4) pyrrolidino, piperidino, morpholino, imidazolyl, substituted        imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆        alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino,        4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino        C₁₋₆ alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆        alkenyl)piperazino;

with the proviso that a) at least one of R₂ and R₃ is selected from [B(ix)] and wherein the substituents are selected from [B (ix) (b)-(d)]above; or b) R₂ and R₃ are taken together to form an optionallysubstituted aryl group, wherein the substituents are defined as above in[B (ix) (a)-(d)];

and R₄ is selected from the group consisting of:

-   -   (i) hydrogen;    -   (ii) substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the        substituents are independently selected from the group        consisting of:        -   (a) hydrogen, hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio, C₁₋₆            alkylamino, phenyl-C₁₋₆ alkylamino, or C₁₋₆ alkoxycarbonyl;        -   (b) substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy, or            substituted C₃₋₆ alkenyloxy;        -   (c) di(C₁₋₆ alkyl)amino, substituted C₁₋₆ alkyl-amino,            di(substituted C₁₋₆ alkyl)amino, C₃₋₆ alkenyl-amino, di(C₃₋₆            alkenyl)amino, substituted C₃₋₆ alkenyl-amino, or            di(substituted C₃₋₆ alkenyl)amino; and    -   (d) pyrrolidino, piperidino, morpholino, imidazolyl, substituted        imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆        alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino,        4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino        C₁₋₆ alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆        alkenyl)piperazino; and    -   (iii) aryl C₀₋₁₁ alkyl wherein the aryl group is selected from        phenyl, imidazolyl, furyl, or thienyl.

In some embodiments of the invention, the compound of Formula 1a is acompound wherein R₁ is selected from the group consisting of mono-, di-,and tri-substituted aryl-C₀₋₆ alkyl wherein aryl is selected from thegroup consisting of phenyl and thienyl, and the substituents areselected from the group consisting of:

-   -   (a) C₁₋₆ CO₂R₅, trans-CH═CHCO₂R₅, C₁₋₆CONHR₅, or        trans-CH═CHCONHR₅;    -   (b) C₁₋₆CONR₆R₇, or trans-CH═CHCONR₆R₇;    -   (c) R₇ C(O)C₁₋₆ alkyl or R₇ C(O)C₂₋₆ alkenyl; and    -   (d) HO—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇—O—C₁₋₆ alkyl-C₂₋₆ alkenyl,        R₇NH—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl,        R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C(O)—O—C₁₋₆        alkyl-C₂₋₆ alkenyl, R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, or        R₇—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl.

In other embodiments, the compound of Formula 1a is a compound whereinR₁ is selected from the group consisting of mono-, di-, andtri-substituted aryl-C₀₋₆ alkyl wherein aryl is selected from the groupconsisting of phenyl and thienyl, and the substituents are selected fromthe group consisting of:

-   -   (a) C₁₋₆ CO₂R₅, trans-CH═CHCO₂R₅, C₁₋₆CONHR₅, or        trans-CH═CHCONHR₅;    -   (b) C₁₋₆CONR₆R₇, or trans-CH═CHCONR₆R₇;    -   (c) R₇ C(O) C₁₋₆ alkyl or R₇ C(O)C₂₋₆ alkenyl; and    -   (d) HO—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇—O—C₁₋₆ alkyl-C₂₋₆ alkenyl,        R₇NH—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl,        R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C(O)—O—C₁₋₆        alkyl-C₂₋₆ alkenyl, R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, or        R₇—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl.

In various embodiments of the invention, the compound of Formula 1a is acompound wherein R₁ is selected from the group consisting of mono-, di-,and tri-substituted aryl-C₀₋₆ alkyl wherein aryl is selected from thegroup consisting of phenyl and thienyl, and the substituents are HO—C₁₋₆alkyl-C₂₋₆ alkenyl, R₇—O—C₁₋₆ alkyl-C₂— alkenyl, R₇NH—C₁₋₆ alkyl-C₂₋₆alkenyl, R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆alkenyl, R₆R₇N—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇O—C(O)—O—C₁₋₆alkyl-C₂₋₆ alkenyl, or R₇—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl.

In other embodiments, R₁ is selected from the group consisting of mono-,di-, and tri-substituted aryl-C₀₋₆ alkyl wherein the aryl-C₀₋₆ alkyl isphenyl-C₀₋₆ alkyl. In some embodiments, R₁ is selected from the groupconsisting of mono-, di-, and tri-substituted aryl-C₀₋₆ alkyl whereinthe aryl-C₀₋₆ alkyl is aryl-C₀alkyl, which is aryl with no alkyl groupattached directly to aryl.

In various embodiments, R₂ and R₃ are each independently selected fromthe group consisting of: mono-, di-, and tri-substituted phenyl whereinthe substituents are independently selected from the group consistingof:

-   -   (i) C₁₋₆ alkyloxy, substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy,        or substituted C₃₋₆ alkenyloxy;    -   (ii) C₁₋₆ alkyl-amino, di(C₁₋₆ alkyl)amino, substituted C₁₋₆        alkyl-amino, di(substituted C₁₋₆ alkyl)amino, C₃₋₆        alkenyl-amino, di(C₃₋₆ (alkenyl)amino, substituted C₃₋₆        alkenyl-amino, or di(substituted C₃₋₆ alkenyl)amino, and    -   (iv) pyrrolidino, piperidino, morpholino, imidazolyl,        substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino,        4-N—C₃— alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆        alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino,        4-N—(C₁₋₆ alkylamino C₁₋₆ alkyl)piperazino, or 4-N—(C₁₋₆        alkylamino C₃₋₆ alkenyl)piperazino.

In some embodiments, R₂ and R₃ are each independently selected from thegroup consisting of: mono-, di-, and tri-substituted phenyl wherein thesubstituents are independently selected from the group consisting ofC₁₋₆ alkyl-amino, di(C₁₋₆ alkyl)amino, substituted C₁₋₆ alkyl-amino,di(substituted C₁₋₆ alkyl)amino, C₃₋₆ alkenyl-amino, di(C₃₋₆alkenyl)amino, substituted C₃₋₆ alkenyl-amino, and di(substituted C₃₋₆alkenyl)amino.

In some embodiments, R₄ is hydrogen.

In some embodiments, the compound of Formula 1a is a compound of Formula1b:

wherein each instance of R_(a) is independently C₁₋₆ alkyl-amino,di(C₁₋₆ alkyl)amino, substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆alkyl)amino, C₃₋₆ alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆alkenyl-amino, or di(substituted C₃₋₆ alkenyl)amino; and

R_(b) is HO—C₁₋₆ alkyl-C₂₋₆ alkenyl R₇—O—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₇NH—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C(O)—O—C₁₋₆ alkyl-C₂₋₆alkenyl, R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, or R₇—C(O)—O—C₁₋₄alkyl-C₂₋₆ alkenyl.

In some embodiments, the compound of Formula 1 or 1a (such as a compoundof Formula 1b or 2), is in the form of a free compound or as itspharmaceutically-acceptable pro-drug, metabolite, analogue, derivative,solvate or salt, and is selected from the group consisting of:(2-[4-(3-ethoxy-1-propenyl)phenyl]-4,5-bis(4-(2-propylamino)phenyl)-TH-imidazole;2-[4-(3-ethoxy-trans-1-pro-pen-1-yl)phenyl]-4,5-bis(4-N,N-diethylaminophenyl)imidazole;2-[4-(3-ethoxy-trans-1-propen-1-yl)phenyl]-4-(4-N,N-diethylaminophenyl)-5-(4-N-methylaminophenyl)imidazole;2-[4-(3-methoxy-trans-1-propen-1-yl)ph-enyl]-4,5-bis(4-pyrrolidinophenyl)imidazole;2-[4-(3-ethoxy-trans-1-prop-en-1-yl)phenyl]-4,5-bis(4-pyrrolidinophenyl)imidazole;2-[4-(3-ethoxy-trans-1-propen-1-yl)phenyl]-4-(4-N-dimethylaminophenyl)-5-(4-pyrrolidinophenyl)imidazole;2-[4-(3-ethoxy-trans-1-propen-1-yl)phenyl-]-4-(4-N-methylaminophenyl)-5-(4-pyrrolidino-phenyl)imidazole;2-[4-(3-ethoxy-trans-1-propen-1-yl)phenyl]-4,5-bis(4-N-morpholinophenyl)imidazole;2-[4-(3-ethoxy-trans-1-propen-1-yl)phenyl]-4-(4-N-dimethylamin-ophenyl)-5-(4-N-morpholinophenyl)imidazole;2-[4-(3-ethoxy-trans-1-propen-1-yl)phenyl]-4-(4-N-methylaminophenyl)-5-(4-N-morpholinophenyl)imidazole;and2-[4-(3-ethoxy-trans-1-propen-1-yl)phenyl]-4-4-N-methylam-nophenyl)-5-(4-N-isopropylaminophenyl)imidazole.

The compound of Formula 1 or 1a can be the specific formulas asdescribed in U.S. Pat. Nos. 5,700,826 and 5,840,721, herein incorporatedby reference. Preferred compositions and methods comprise the compoundof the following formula (Formula 2):

in the form of a free compound or as its pharmaceutically-acceptablepro-drug, metabolite, analogue, derivative, solvate or salt.

The compounds of Formula 1 or 1a (such as a compound of Formula 1b or 2)are synthesized by any suitable method known in the field. Examples ofthe synthesis for this class of compounds and the compound of Formula 2,in particular, are disclosed in U.S. Pat. No. 5,840,721, which is herebyincorporated by reference in its entirety.

The compounds of the present invention modulate GSL synthesis and/ormetabolism. The compounds can prevent accumulation of complex GSLs. Thecompounds can inhibit longer chain GSL formation, or complex GSLformation. The compounds can modulate GSL synthesis and/or metabolism bymodulating the activity of an ABC transporter involved in GSLbiosynthesis. The ABC transporter can be the P-glycoprotein, encoded bythe MDR1 gene. MDR1 encodes a 170 kDa membrane alycoporotein (gp-170 orPgp) that typically acts as an ATP-dependent efflux pump, transporting anumber of unrelated organic compounds out of the cell (Juranka et al.,FASEB J. 3:2583-2592 (1989)). The level of expression of gp-170 has beenshown to correlate with the degree of drug resistance (Raderer andSscheitharer, Cancer 72: 3553-3563 (1993)). Gp-170 appears to act as apump that actively extrudes a wide variety of structurally unrelatedcompounds, including a full range of antineoplastic drugs. AnotherATP-dependent membrane efflux pump, the product of the MRP gene, hasalso been implicated in the MDR phenomenon (Krishnamachary and Center,Cancer Res. 53:3658-3661 (1993)), as have other ATP-dependent andenzymatic mechanisms.

Drugs of proven antitumor chemotherapeutic value to which MDR has beenobserved include vinblastine, vincristine, etoposide, teniposide,doxorubicin (adriamycin), daunorubicin, pliamycin (mithramycin), andactinomycin D (Jones et al., Cancer (Suppl) 72:3484-3488 (1993)). Manytumors are intrinsically multidrug resistant (e.g., adenocarcinomas ofthe colon and kidney) while other tumors acquire MDR during the courseof therapy (e.g., neuroblastomas and childhood leukemias). Recently, ithas been shown that MDR cells, as opposed to drug-sensitive cells,display increased levels of glucosylceramide (Lavie et al, J. Biol.Chem. 271:19530-19536271:19530-19536 (1996)) and further MDR modulatorsmay increase the cellular susceptibility to chemotherapeutic agentsthrough regulation of ceramide metabolism in cancer cells (Lavie et al.,J. Biol. Chem. 272:1682-1687 (1997)). Accumulation of glucosylceramide(GlcCer), a simple glycosylated form of ceramide, is a characteristic ofsome MDR cancer cells and tumors derived from patients who are lessresponsive to chemotherapy (Lavie et at., J. Biol. Chem. 271:19530-19536(1996); Lucc et al., Anticancer Res. 18: 475-480 (1998)). Modificationof ceramide metabolism, by blocking the glycosylation pathway, has beenshown to increase cancer cell sensitivity to cytotoxics (Lucci et ax,Int. J. One. 15: 541-546 (1999); Lavie et al., J. Biol. Chem.272:1682-1687 (1997); Lucci et al., Cancer 86:299-310 (1999)). Further,drug combinations that enhance ceramide generation and limitglycosylation have been shown to enhance kill in cancer cell models(Lavie et at, J. Biol. Chem. 272:1682-1687 (1997); Lucci et al., Cancer86:299-310 (1999)). Other work has shown that ceramide toxicity can bepotentiated in experimental metastasis of murine Lewis lung carcinomaand human neuroepithelioma cells by inclusion of a glucosylceramidesynthase inhibitor (Inokuchi et al., Cancer Res. 50: 6731-6737 (1990);Spinedi et al, Cell Death Differ. 5:785-791 (1998)).

Compounds described herein can modulate GSL levels by effecting MDR1activity. The compounds can provide increased specificity for modulatingGlcCer levels, as compared to modulating MDR. For example, a variety ofstructurally diverse agents have been identified which can restorepartly or sometimes completely the normal drug sensitivity to some MDRtumor cells. These chemosensitizers are effective as a result of theirability to interfere with gp-170, causing a reversal in the increase indrug efflux, but among these agents are calcium channel blockers (e.g.,verapamil), calmodulin inhibitors (e.g., trifluoperazine), antibiotica(e.g., erythromycin), cardiovascular agents (e.g., quinidine),noncytotoxic analogs of anthracyclines and vinca alkaloids, cyclosporinA and analogs thereof, FK-506 and analogs thereof, and derivatives ofcyclopeptides (Lum et al, Cancer (Suppl) 72:3502-3514 (1993)). Many ofthese agents have not provided a significant contribution to thechemotherapeutic index for the treatment of cancer due to theirsignificant pharmacological effects on other organ systems. Compounds ofthe present invention may be specific for the translocation or flippaseactivity of the MDR1 that affects GSL synthesis, rather than thereversal of MDR, and may also have a lack of significant toxicity andother nonspecific pharmacological effects. Alternatively, compounds mayaffect both, but have a greater effect on GSL levels rather than MDR.

For example, cells exhibiting abnormal GSL metabolism can be treatedwith the compounds of the present invention at a concentration or dosagethat modulates GlcCer levels, but would not affect MDR in cancer cells.The compound administered to subjects suffering from GSL metabolismdisorders can ameliorate symptoms of GSL disorder, but not MDR ofsubjects suffering from cancer. Therapeutically effective dosages of thecompounds of the present invention can have an effect on GSL disordersymptoms, but not on MDR. In some embodiments, the compounds mayspecifically modulate the levels of specific GSL, for example neutralGSLs or acidic GSLs, or both, in which other MDR inhibitors do not. Thecompounds can have a higher specificity or increased activity inaffecting GSL as compared to other MDR inhibitors, and thus moreeffective in treating GSL metabolism disorders. Dosages and toxicitiescan also vary between compounds that are used for treating GSL disordersas compared to composed used in treating MDR with MDR1 inhibitors.

Combinations of compounds of the present invention are also provided. Inpreferred embodiments, combinations have a synergistic effect. Thepresent invention contemplates administering the compounds with any ofseveral different kinds of compounds. These include, for example,substrate competitors for enzyme inhibition therapy, enzymes for enzymereplacement therapy, gene therapy and chaperones for enzymes. Forexample, a composition of the present invention can comprise a firstcompound of Formula 1 or 1a as described herein (for example, a compoundof Formula 1b or 2), with a second compound that is a glucosylceramidesynthase inhibitor. In some embodiments, the glucosylceramide synthaseinhibitor is miglustat, or,1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol. Another compounds thatcan be used is PDMP(1R-phenyl-2R-decanoylamino-3-morpholino-1-propanol), previouslyidentified as the D-threo isomer (Inokuchi et al., J. Lipid Res.28:565-571 (1987)), that has been found to produce a variety of chemicaland physiological changes in cells and animals (Radin et al., “Use of1-Phenyl-2-Decanoylamino-3-Morpholino-1-Propanol (PDMP), an Inhibitor ofGlucosylceramide Synthesis,” In NeuroProtocols, A Companion to Methodsin Neurosciences, S. K. Fisher et al., Ed., (Academic Press, San Diego)3:145-155 (1993) and Radin et al., “Metabolic Effects of InhibitingGlucosylceramide Synthesis with PDMP and Other Substances,” In Advancesin Lipid Research; Sphingolipids in Signaling, Part B., R. M. Bell etal., Ed. (Academic Press, San Diego) 28:183-213 (1993)). Homologs,analogs, or derivatives of PDMP can also be used, such as the P4compound (1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol). (Shaymanet al., J. Biol. Chem., 277:18447-18453 (2002); Asano, Glycobiology13:93R-104R (2003); Jimbo et al, J. Biochem. (Tokyo) 127:485-491(2000)). Imino sugar-based glucosylceramide synthase inhibitors, such asN-butyldeoxynojirimycin, may also be used.

In some embodiments, treatment of GSL disorders comprise administeringcompositions comprising the compound of the present invention along withenzyme-replacement therapy (ERT), for example with imiglucerase (ananalogue of human β-glubcocerebrosidase) or α-galactosidase (Brady, ActaPaediatr. Suppl. 92:19-24 (2003); Heukamp et al., Pathol. Res. Pract.199:159-163 (2003); Wilcox et al., Am. J. Hum. Genet. 75:(65-74)(2004)). Combinatorial treatments also include gene therapy, forexample, a patient with Fabry disease can be treated with a recombinantretrovirus carrying the cDNA encoding the defective α-Gal A that is usedto transfect skin fibroblasts obtained from the Fabry patient (Medin etal., Proc. Natl. Acad. Sci. USA 93:7917-7922 (1996)) along with thecompound of the present invention.

In another embodiment, the compound of Formula 1 or 1a (such as acompound of Formula 1b or 2) is administered in combination with achaperone. Chaperones have an important role in protein folding.Misfolded proteins are typically eliminated by cellular quality controlmechanisms, or accumulate and affect protein trafficking. Artificalchaperones used in combination with the compound of the presentinvention include non-specific chemical chaperones, such as highconcentrations of glycerol, dimethylsulfoxide, trimethylamine N-oxide,or deuterated water have been shown to stabilize the mutant protein andincrease the intracellular trafficking of mutant protein in severaldiseases (Brown et al., Cell Stress Chaperones 1:117-125 (1996); Burrowset al, Proc. Natl. Acad. Sci. USA; 97:1796-1801 (2000)). Pharmacologicalchaperones which bind to the enzyme and promote trafficking of theenzyme from the endoplasmic reticulum to the lysosome can be used. Inpreferred embodiments, the compound of Formula 1 is adminstered withactive site specific chaperones (ASSC). ASSCs known in the art, such as1-deoxygalactonojirimycin (DGJ) (U.S. Pat. Nos. 6,274,597, and6,774,135), can be used. ASSCs are thought to stabilize misfoldedproteins thus, enabling proper protein conformation for trafficking tothe lysosomes, and thus ASSCs aid in ameliorating LSDs (U.S. Pat. Nos.6,583,158, 6,589,964, 6,599,919). Other ASSCs include glucoimidazole(GIZ) and polyhydroxycyclohexenyl amine (PHCA) derivatives (U.S. Pat.Appln. No. 20050137223), which may be used in combination with thecompound of the present invention for treating diseases associated withmutant glucocerebrosidase, such as Gaucher's. Hydroxy piperidine (HP)derivatives (U.S. Pat. Appln. 20050130972) can also be used incombination with the compound of Formula 1 or 1a (for example, acompound of Formula 1b or 2), in treating individuals having Gaucherdisease.

II. Conditions Characterized by Disorders in GSL Metabolism

The importance of treating GSL metabolism disorders is underscored byvarious important roles sphingolipids have. Sphingolipids are ubiquitousconstituents of membrane lipids in mammalian cells. Sphingolipids areinvolved in membrane trafficking and intracellular signaling as a factorrequiring for the formation of membrane micro domains so called lipidrafts. In addition to being the building blocks of biological membranes,glycosphingolipids appear to be involved in cell proliferation (Hannunand Bell, Science, 243:500-507 (1989)) differentiation (Schwarz et al.,J. Biol. Chem. 270:10990-10998 (1995); Harel and Futerman, J. Biol.Chem. 268:14476-14481 (1993)), oncogenic transformation (Hakomori, Annu.Rev. Biochem. 50:733-764 (1981); Morton et al, Prog. Brain Res.101:251-275 (1994)) and the prevention of the onset of apoptosis(Nakamura et al., J. Biol. Chem. 271:1255-1257 (1996)).

The biosynthesis process of sphingolipids in mammalian cells may be asillustrated in FIG. 1. The first step depicts the condensation reactionof L-serine with palmitoyl CoA. The reaction is catalyzed by serinepalmitoyl transferase to generate 3-ketodihydrosphingosine. Theresulting 3-ketodihydrosphingosine is then reduced todihydrosphingosine. The obtained dihydrosphingosine can then undergoN-acylation followed by desaturation to generate ceramide (Cer). Thesereactions to produce Cer typically occur on the cytosolic surface of theendoplasmic reticulum (ER). Cer is then thought to be delivered to thelumenal side of the Golgi apparatus and converted to sphingomyelin (SM)by SM synthase catalyzing transfer of phosphocholine fromphosphatidylcholine (PC) to Cer. Cer is also converted toglucosylceramide (GlcCer). Glucosylceramides are produced byglucosylceramide synthase (GCS) transferring glucose from UDP-glucose toceramide (Basu, et al, (1968) J. Biol. Chem. 243:5802-5804). The rate ofGlcCer formation under physiological conditions usually depends on thetissue level of UDP-glucose, which in turn depends on the level ofglucose in a particular tissue (Zador et al., J. Clin. Invest.91:797-803 (1993)). In vitro assays based on endogenous ceramidetypically yield lower synthetic rates than mixtures containing addedceramide, suggesting that tissue levels of ceramide are also normallyrate-limiting (Brenkert et al, Brain Res. 36.183-193 (1972)).

However, unlike many other GSLs, GlcCer is typically made on the outerleaflet of the Golgi bilayer (Lannert et al., J. Biol. Chem.273:2939-2946 (1998)). As a result, for GlcCer to be accessed byglycosyltransferases for further carbohydrate elongations, GlcCertypically needs to be translocated, or “flipped”, into the lumen of theGolgi. MDR1 can function as a glycolipid flippase and appears to beresponsible for the translocation of GlcCer into the lumen for furthercarbohydrate elongation. MDR1 translocation appears to be specific forneutral GSL synthesis (DeRosa et al. J. Biol. Chem. 279:7867-7876(2004)). Compounds of the present invention can specifically inhibit thetranslocation or flippase function of MDR1, or may be specific formodulating neutral GSL synthesis, acidic GSL synthesis, or both. Forexample, the compound can inhibit Gb3 accumulation but not gangliosides,whereas other compounds inhibit accumulation of both Gb3 andgangliosides.

Most glycosphingolipids (GSLs) are derived from glucosylceramide(GlcCer). GSLs are a subtype of glycolipids containing the amino alcoholsphingosine, and include cerebrosides, gangliosides, and globosides.Cerebrosides are important components of animal and muscle nerve cells,and include myelin. Gangliosides are GSLs with one or more sialic acids,common gangliosides being GD1a, GD1b, GD2, GD3, GM1, GM2, GM3, and GT1b.Gangliosides are a component of the plasma membrane and modulate cellsignal transduction events. They are also present in lipid rafts.Globosides are GSLs with N-acetyglactosamine as the side chain.Sphingomyelin is present in animal cell membranes and may have a role insignal transduction. Defects in the metabolism of GSLs can lead todifferent diseases, for example, a defect in the degradation ofglucocerebrosides can cause Gacuher's, defect in galactocerebrosides cancause Karbbe disease. Gangliosides are imported in immunology and may beinvolved in neurodegenerative diseases. Defects in β-hexosadminidase,which cleaves the side chain of globosides, can lead to Sandhoffdisease, and sphingomyelin accumulation can lead to Niemann-Pickdisease.

The compositions and methods described herein are effective in treatingGSL metabolic conditions, which may specifically inhibit thetranslocation or flippase function of MDR1, or may be specific formodulating neutral GSL synthesis. In some aspects, conditions due to anydefective enzyme, or abnormal levels of substrates/products of the GSLbiosynthesis pathways, may be treated. Conditions include Gaucher(GlcCer accumulation) and Fabry (globotraiosyl, or Gb3, accumulation),as well as other lysosomal storage diseases including, but not limitedto, Niemann-Pick, Tay Sachs, and Sandhoff's disease. Other diseases withimpaired glycosylated proteins, such as cystic fibrosis, can also betreated by compositions and methods of the present invention.

Many known lysosomal storage diseases (LSDs) involve a similarpathogenesis, namely, a compromised lysosomal hydrolase. Generally, LSDsare due to genetic deficiencies in glycoconjugate catabolism, which maybe due to the activity of a single lysosomal hydrolytic enzyme, such asa specific lysosomal sugar hydrolase or its activator protein, beingreduced or lacking altogether. The substrate of the compromised enzymeaccumulates undigested in lysosomes, producing severe disruption ofcellular architecture and various disease manifestations. A number ofsphingolipidoses, group of LSDs caused by deficient activity oflysosomal enzymes crucial for the degradation of sphingolipids, is shownin Table 1, and may be treated by the compositions and methods of thepresent invention. For example, in “glycosphingolipidoses”, accumulationtypically results in the formation of lipid inclusions and multilamellarstructures that prevent normal cell functions. LSDs can be classified bythe nature of their storage material, such as lipid storage disorders(including Gaucher's and Nieman-Pick), gangliosidoses (such as Tay-Sachsdisease), leukodystrophies, mucopolysaccharidoses (including Huntersyndrome and Hurler disease), glycoprotein storage disorders, andmucolipidoses.

Gaucher's disease is one of the most common lysosomal storage diseasesknown. Type 1 is usually the most common among three recognized clinicaltypes and typically follows a chronic course which does not involve thenervous system. Types 2 and 3 both have a CNS component, the formertypically being an acute infantile form with death by age two and thelatter a subacute juvenile form. The incidence of Type 1 Gaucher'sdisease is about one in 50,000 live births and about one in 400 livebirths among Ashkenazis (Kolodny et al., 1998, “Storage Diseases of theReticuloendothelial System”, In: Nathan and Oski's Hematology of Infancyand Childhood, 5th ed., vol. 2, David G. Nathan and Stuart H. Orkin,Eds., W. B. Saunders Co., pages 1461-1507). Also known asglucosylceramide lipidosis, Gaucher's disease is typically caused byinactivation of the enzyme glucocerebrosidase and accumulation ofglucocerebroside (also known as GlcCer). Glucocerebrosidase normallycatalyzes the hydrolysis of glucocerebroside to glucose and ceramide. InGaucher's disease, glucocerebroside accumulates in tissue macrophageswhich become engorged and are typically found in liver, spleen and bonemarrow and occasionally in lung, kidney and intestine. Secondaryhematologic sequelae include severe anemia and thrombocytopenia inaddition to the characteristic progressive hepatosplenomegaly andskeletal complications, including osteonecrosis and osteopenia withsecondary pathological fractures.

Niemann-Pick disease, also known as sphingomyelin lipidosis, comprises agroup of disorders characterized by foam cell infiltration of thereticuloendothelial system. Foam cells in Niemann-Pick become engorgedwith sphingomyelin and, to a lesser extent, other membrane lipidsincluding cholesterol. Niemann-Pick is typically caused by inactivationof the enzyme sphingomyelinase in Types A and B disease, with 27-foldmore residual enzyme activity in Type B. The pathophysiology of majororgan systems in Niemann-Pick can be briefly summarized as follows. Thespleen is the most extensively involved organ of Type A and B patients.The lungs are involved to a variable extent, and lung pathology in TypeB patients is the major cause of mortality due to chronicbronchopneumonia. Liver involvement is variable, but severely affectedpatients may have life-threatening cirrhosis, portal hypertension, andascites. The involvement of the lymph nodes is variable depending on theseverity of disease. Central nervous system (CNS) involvementdifferentiates the major types of Niemann-Pick. While most Type Bpatients do not experience CNS involvement, it is characteristic in TypeA patients. The kidneys are only moderately involved in Niemann Pickdisease.

Fabry disease is an X-linked recessive LSD characterized by a deficiencyof α-galactosidase A (α-Gal A), also known as ceramide trihexosidase,which leads to vascular and other disease manifestations viaaccumulation of glycosphingolipids with terminal α-galactosyl residues,such as globotriaosylceramide (GL-3, or Gb3) (see generally Desnick R Jet al., 1995, α-galactosidase A Deficiency: Fabry Disease, In: TheMetabolic and Molecular Bases of Inherited Disease, Scriver et al.,eds., McGraw-Hill, New York, 7.sup.th ed., pages 2741-2784). Symptomsmay include anhidrosis (absence of sweating), painful fingers, leftventricular hypertrophy, renal manifestations, and ischemic strokes. Theseverity of symptoms varies dramatically (Grewal, J. Neurol. 241:153-15(1994)). A variant with manifestations limited to the heart isrecognized, and its incidence may be more prevalent than once believed(Nakao. N. Engl. J. Med. 333:288-293 (1995)).

Tay-Sachs disease, also known as GM2 gangliosidosis or hexosaminidase Adeficiency, is a genetic disorder wherein the most common variant,infantile Tay-Sachs disease, is fatal. The disease is typically causedby mutations on the HEXA gene. The HEXA gene encodes the α-subunit ofthe lysosomal enzyme β-hexosaminidase A. Hydrolysis of GM2-gangliosidetypically requires three proteins. two subunits of hexosaminidase A, anda small glycolipid transport protein, the GM2 activator protein (GM2A),which acts as a substrate specific cofator for the enzyme. Deficiency inany one of these proteins leads to storage of the ganglioside, primarilyin the lysosomes of neuronal cells lysosomes of neuronal cells.Deficiencies in hexosaminidase A caused by HEXA mutations can lead toTay-Sachs disease.

Patients with Sandhoff's disease have similar symptoms to Tay-Sachs.Sandhoff's is a lipid storage disorder that causes progressivedestruction of nerve cells. The disease is typically inherited andinvolves the CNS and involves mutations in the HEXB gene which encodesthe β-subunit of the lysosomal enzymes β-hexosaminidase A and B. Thus,HEXB mutations can affect both β-hexosaminidase A and B and preventbreakdown of GM2 gangliosides and other molecules leading toaccumulation of these molecules, causing nerve cell destruction anddisease.

Diseases and conditions other than LSDs are also treated by thecompositions and methods of the present invention. For example, otherdiseases resulting from, or which result in, increased glycosphingolipidsynthesis can be treated, such as cystic fibrosis. Cystic fibrosis (CF)epithelial cells express a greater density of an asialylated ganglioside(gangliotetraosyl ceramide, Gg4), on their apical surface, whichmanifest as a higher susceptibility of CF individuals of acquiringbacterial infections. (Hart and Winstanley, British Medical Bulletin61:81-96 (2002)).

The compounds of Formula 1 or 1a (such as Formula 1b or 2), can be usedto treat other conditions by inhibiting GSL synthesis, such asconditions associated with bacteria. For example, administration of thecompounds of the present invention may reduce cell sensitivity, and thusconditions associated with verotoxin (or Shiga toxin), cholera toxin, oruropathic E. coli. Verotoxins are thought to inhibit protein synthesisin cells and may have a role in hemorrhagic colitis and hemolytic uremicsyndrome, by damaging endothelial cells in the kidney and brain. Acomponent of the verotoxin is believed to inhibit protein synthesis bybinding Gb3 and enters the cell. Cholera toxin, believed to be the causeof the major characteristics of cholera, is thought to enter cells bybinding GM1. Uropathic E. coli may bind globo series GSLs. Without beingbound by theory, reducing GSL synthesis may reduce the ability of thetoxins, or infectious bacteria, to enter the cell, thereby decreasingtheir negative effects.

For treatment, the compounds of Formula 1 or 1a (such as a compound ofFormula 1b or 2), can be administered before, after, before and after,and/or simultaneously with another compound as described herein. Thecompounds of Formula 1 or 1a (such as a compound of Formula 1b or 2) canbe administered in the form of a free compound or apharmaceutically-acceptable pro-drug, metabolite, analogue, derivative,solvate or salt are useful in the treatment of conditions related todefective GSL metabolism, such as MDR related LSDs, either separately orin combination with another agent or therapy, such as ERT. Thesecompounds can be administered orally, topically or parenterally indosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants, and vehicles. The termparenteral as used herein includes subcutaneous injections, aerosol,intravenous, intramuscular, intrathecal, intracranial, intrasternalinjection or infusion techniques.

The present invention also has the objective of providing suitabletopical, oral, and parenteral pharmaceutical formulations for use in thenovel methods of treatment of the present invention. The compounds ofthe present invention may be administered orally as tablets, aqueous oroily suspensions, lozenges, troches, powders, granules, emulsions,capsules, syrups or elixirs. The composition for oral use may containone or more agents selected from the group of sweetening agents,flavoring agents, coloring agents and preserving agents in order toproduce pharmaceutically elegant and palatable preparations. The tabletscontain the acting ingredient in admixture with non-toxicpharmaceutically acceptable excipients that are suitable for themanufacture of tablets. These excipients may be, for example, (1) inertdiluents, such as calcium carbonate, lactose, calcium phosphate,carboxymethylcellulose, or sodium phosphate; (2) granulating anddisintegrating agents, such as corn starch or alginic acid; (3) bindingagents, such as starch, gelatin or acacia; and (4) lubricating agents,such as magnesium stearate, stearic acid or talc. These tablets may beuncoated or coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate may be employed. Coatingmay also be performed using techniques described in the U.S. Pat. Nos.4,256,108; 4,160,452; and 4,265,874 to form osmotic therapeutic tabletsfor control release.

Administration may be intravenously, intraperitoneally, intramuscularly,subcutaneously, intracavity, or transdermally. For in vitro studies, thecompounds may be added or dissolved in an appropriate biologicallyacceptable buffer and added to a cell or tissue.

Preparations for parenteral administration include sterile aqueous ornon-aqueous solutions, suspensions, and emulsions. Examples ofnon-aqueous solvents are propylene glycol, polyethylene glycol,vegetable oils such as olive oil, and injectable organic esters such asethyl oleate. Aqueous carriers include water, alcoholiclaqueoussolutions, emulsions or suspensions, including saline and bufferedmedia. Parenteral vehicles include sodium chloride solution, Ringer'sdextrose, dextrose and sodium chloride, lactated Ringer's intravenousvehicles include fluid and nutrient replenishers, electrolytereplenishers (such as those based on Ringer's dextrose), and the like.Preservatives and other additives may also be present such as, forexample, antimicrobials, anti-oxidants, chelating agents, growth factorsand inert gases and the like.

Therefore, the present invention encompasses methods for amelioratingdiseases and conditions, including but not limited to disordersassociated with abnormal or defective GSL synthesis, with a compound ofFormula 1 or 1a (such as a compound of Formula 1b or 2), in the form ofa free compound or a pharmaceutically-acceptable pro-drug, metabolite,analogue, derivative, solvate or salt, and a chemotherapeutic orpharmaceutical agent in an amount sufficient to inhibit or amelioratethe cell's proliferation or the disorder. Generally, the terms“treating”, “treatment” and the like are used herein to mean affecting asubject, tissue or cell to obtain a desired pharmacologic and/orphysiologic effect. The effect may be prophylactic in terms ofcompletely or partially preventing a disease or sign or symptom thereof,and/or may be therapeutic in terms of a partial or complete cure for adisorder and/or adverse effect attributable to, for example, aberrantcell proliferation. “Treating” as used herein covers any treatment of,or prevention of a disease or disorder in a vertebrate, a mammal,particularly a human, and includes: (a) preventing the disease ordisorder from occurring in a subject that may be predisposed to thedisease or disorder, but has not yet been diagnosed as having it; (b)inhibiting the disease or disorder, i.e., arresting its development; or(c) relieving or ameliorating the disease or disorder, i.e., causeregression of the disease or disorder.

The present invention includes various pharmaceutical compositionsuseful for ameliorating diseases and disorders related to GSLmetabolism, including LSDs and the like. The pharmaceutical compositionsaccording to one embodiment of the invention are prepared by bringing acompound of Formula 1 or 1a (such as a compound of Formula 1b or 2), inthe form of a free compound or a pharmaceutically-acceptable pro-drug,metabolite, analogue, derivative, solvate or salt, and optionally, oneor more pharmaceutical agents or combinations of the compound of Formula1 or 1a (such as a compound of Formula 1b or 2), into a form suitablefor administration to a subject using carriers, excipients and additivesor auxiliaries. Frequently used carriers or auxiliaries includemagnesium carbonate, titanium dioxide, lactose, mannitol and othersugars, talc, milk protein, gelatin, starch, vitamins, cellulose and itsderivatives, animal and vegetable oils, polyethylene glycols andsolvents, such as sterile water, alcohols, glycerol and polyhydricalcohols. Intravenous vehicles include fluid and nutrient replenishers.Preservatives include antimicrobial, anti-oxidants, chelating agents andinert gases. Other pharmaceutically acceptable carriers include aqueoussolutions, non-toxic excipients, including salts, preservatives, buffersand the like, as described, for instance, in Remington's PharmaceuticalSciences, 15th ed. Easton: Mack Publishing Co., 1405-1412, 1461-1487(1975) and The National Formulary XIV, 14th ed. Washington: AmericanPharmaceutical Association (1975), the contents of which are herebyincorporated by reference. The pH and exact concentration of the variouscomponents of the pharmaceutical composition are adjusted according toroutine skills in the art. See Goodman and Gilman's The PharmacologicalBasis for Therapeutics (7th ed.).

The pharmaceutical compositions are preferably prepared and administeredin dose units. Solid dose units are tablets, capsules and suppositories.For treatment of a subject, depending on activity of the compound,manner of administration, nature and severity of the disorder, age andbody weight of the subject, different daily doses can be used. Undercertain circumstances, however, higher or lower daily doses may beappropriate. The administration of the daily dose can be carried outboth by single administration in the form of an individual dose unit orelse several smaller dose units and also by multiple administration ofsubdivided doses at specific intervals.

The pharmaceutical compositions according to the present invention maybe administered locally or systemically in a therapeutically effectivedose. Amounts effective for this use will, of course, depend on theseverity of the disease and the weight and general state of the subject.Typically, dosages used in vitro may provide useful guidance in theamounts useful for in situ administration of the pharmaceuticalcomposition, and animal models may be used to determine effectivedosages for treatment of particular disorders. Various considerationsare described, e.g., in Langer, Science, 249:1527, (1990); Gilman et al.(eds.) (1990), each of which is herein incorporated by reference.Dosages for parenteral administration of active pharmaceutical agentscan be converted into corresponding dosages for oral administration bymultiplying parenteral dosages by appropriate conversion factors. As togeneral applications, the parenteral dosage in mg/m² times 1.8 may equalthe corresponding oral dosage in milligrams (“mg”). See the Miller-KeaneEncyclopedia & Dictionary of Medicine, Nursing & Allied Health, 5.sup.thEd., (W.B. Saunders Co. 1992). pp. 1708 and 1651.

The method by which the compound of Formula 1 or 1a (such as a compoundof Formula 1b or 2) may be administered for oral use would be, forexample, in a hard gelatin capsule wherein the active ingredient ismixed with an inert solid diluent, for example, calcium carbonate,calcium phosphate or kaolin. They may also be in the form of softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, such as peanut oil, liquid paraffin or olive oil. The activeingredient can be mixed with a co-solvent mixture, such as PEG 400containing Tween-20. A compound of Formula 1 or 1a (such as a compoundof Formula 1b or 2) can also be administered in the form of a sterileinjectable aqueous or oleaginous solution or suspension. The compound ofFormula 1 or 1a (such as a compound of Formula 1b or 2), can generallybe administered intravenously or as an oral dose of 0.5 to 10 mg/kggiven every 12 hours, 1 to 3 times a day, or may be given before and 1to 3 times after the administration of another pharmaceutical agent,with at least one dose 1 to 4 hours before and at least one dose within8 to 12 hours after the administration of the other agent.

Aqueous suspensions normally contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspension. Suchexcipients may be (1) suspending agent such as sodium carboxymethylcellulose, methyl cellulose, hydroxypropylmethylcellulose, sodiumalginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; (2)dispersing or wetting agents which may be (a) naturally occurringphosphatide such as lecithin; (b) a condensation product of an alkyleneoxide with a fatty acid, for example, polyoxyethylene stearate; (c) acondensation product of ethylene oxide with a long chain aliphaticalcohol, for example, heptadecaethylenoxycetanol; (d) a condensationproduct of ethylene oxide with a partial ester derived from a fatty acidand hexitol such as polyoxyethylene sorbitol monooleate, or (e) acondensation product of ethylene oxide with a partial ester derived fromfatty acids and hexitol anhydrides, for example polyoxyethylene sorbitanmonooleate.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to known methods using those suitable dispersing orwetting agents and suspending agents that have been mentioned above. Thesterile injectable preparation can be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

A compound of Formula 1 or 1a (such as a compound of Formula 1b or 2),can also be administered in the form of suppositories for rectaladministration of the drug. These compositions can be prepared by mixingthe drug with a suitable non-irritating excipient that is solid atordinary temperature but liquid at the rectal temperature and willtherefore melt in the rectum to release the drug. Such materials includecocoa butter and polyethylene glycols.

The compounds of Formula 1 or 1a (such as a compound of Formula 1b or2), as used in the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of Formula 1 or 1a (such as a compound ofFormula 1b or 2), may be employed.

Dosage levels of the compounds of Formula 1 or 1a (such as a compound ofFormula 1b or 2), as used in the present invention may be of the orderof about 0.5 mg to about 20 mg per kilogram body weight, an averageadult weighing 70 killograms, with a preferred dosage range betweenabout 5 mg to about 20 mg per kilogram body weight per day (from about0.3 gms to about 1.2 gms per patient per day). The amount of thecompound of Formula 1 or 1a (such as a compound of Formula 1b or 2) thatmay be combined with the carrier materials to produce a single dosagewill vary depending upon the host treated and the particular mode ofadministration. For example, a formulation intended for oraladministration to humans may contain about 5 mg to 1 g of a compound ofFormula 1 or 1a (such as a compound of Formula 1b or 2) with anappropriate and convenient amount of carrier material that may vary fromabout 5 to 95 percent of the total composition. Dosage unit forms willgenerally contain between from about 5 mg to 500 mg of Formula 1 or 1a(such as a compound of Formula 1b or 2), of active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

In addition, some of the compounds of the instant invention may formsolvates with water or common organic solvents. Such solvates areencompassed within the scope of the present invention

In further embodiments the invention provides compositions comprising acompound of Formula 1 or 1a (such as a compound of Formula 1b or 2), inthe form of pharmaceutically-acceptable pro-drugs, metabolites,analogues, derivatives, solvates or salts in admixture with an activepharmaceutical agent or chemotherapeutic agent, together with apharmaceutically acceptable diluent, adjuvant, or carrier.

TABLE 1 Major Sphingolipidoses Clinical diagnosis Affected lipids Enzymedefect GM1 gangliosidosis GM1 ganglioside β-Galactosidase Galactose-richfragments of glycoproteins GM2 gangliosidosis GM2 gangliosideβ-Hexosaminidase A Tay-Sachs disease, B variant GM2 gagliosideβ-Hexosaminidase B1 variant GM2 gaglioside GM2 activator protein ABvariant GM2 gaglioside, β-Hexosamimdase A, B Sandhoff's disease, Ovariant Asialo GM2 ganglioside, Globoside Niemann-Pick disease (A and B)Sphingomyelin Sphingomyelinase Gaucher's disease GlucosylceramideGlucosylceramidase Gluccosylsphingosine Farber's disease Ceramide Acidceramidase Fabry's disease Trihexosylceramide a-Galactosidase AMetachromatic leukodystrophy Sulfatide Arylsulfatase A Multiplesulfatase deficiency Sulfatide and other compounds Arylsulfatase A, B, Cand others Globoid cell leukodystrophy GalactosylceramideGalactosylceramidase (Krabbe's disease) Galactosylsphingosine Total SAPdeficiency Multiple sphingolipids Sphingolipid activator protein SAP-Bdeficiency Sulfatide and others Sulfatidase activator (SAP-B) SAP-Cdeficiency Glucosylceramide SAP-C

EXAMPLES Example #1 Effect of Compound of Formula 2 on Cultured CellGSLs

Cultured Gaucher and/or Fabry B-cell lines were treated with 0, 4, or 8μM of the compound of Formula 2 for 3 days. The GSL fractions werepurified and separated by thin layer chromatography (TLC). GSL fractionswere detected by orcinol spray. (FIG. 2). At 4 μM there was a decreasein Gb3 levels and increased LacCer and GlcCer levels, suggestingtranslocation of GlcCer into the Golgi was inhibited, preventing longerchain GSL formation and/or increased GSL breakdown into LcCer andGlcCer. At 8 TOM, comlpex GSL levels were significant reduced.

Example #2 Treatment of Fabry Mice with Compound of Formula 2

Eight control neonatal Fabry mice (5 male and 3 female) were injected ipbi-weekly one week from birth with saline, and eight experimental Fabrymice (4 male and 4 female) were injected ip bi-weekly one week frombirth with Formula 2 (20 mg/kg) in saline, for a period of 10 weeks.After this time, the mice were euthanized by anaesthetic overdose.Tissues from the mice were removed and frozen for later glycolipidanalysis. Samples of each tissue were also frozen in OCT mounting mediumand frozen sections of the livers of all animals were processed. Gb3expression in the frozen liver sections was determined using VT1 sectionstaining using verotoxin staining (as described in Mattocks et al., FEBSJ. 273:2064-2075 (2006)), such that the Gb3 positive tissue structuresare stained brown and the sections are counter stained withhematoxylin/eosin. All controls sections were similar. Intense stainingof the stellate Kupffer cells (see FIG. 3, arrows) as previouslyreported (Mattocks et al., FEBS J. 273:2064-2075 (2006)) was detectedtogether with strong staining of endothelial cells lining the hepaticportal (see FIG. 3, p) and central veins (see FIG. 3, *). In seven ofeight of the experimental animals, there was essentially no residualstaining for Gb₃ within the liver. In one animal, some diffuse Gb3staining remained but even in this animal, the staining was considerablyless than in the control group.

Treating neonatal mice with Formula 2 was more effective in reducingliver Gb3 staining as compared to mice treated with cyclosporine (FIG.3, Formula 2 treated Fabry mice compared to CsA treated Fabry mice).Kupffer cell staining of mice treated with cyclosporine, although lessintense, was still present. Similarly, residual endothelial cellstaining (particularly in portal veins which were refractory) in somemice treated with cyclosporine remained in evidence.

Since Kupffer cells are scavenger macrophage-like cells, it is possiblethat their Gb3 content reflects the level of Gb3 in the serum ratherthan (or in addition to) endogenous synthesis by the Kupffer cellsthemselves. As treatment with Formula 2 essentially removed Gb3 from theliver Kupffer cells, the circulating level of Gb3 in these treated miceis likely also reduced to normal background levels.

Treatment of Fabry mice with Formula 2 was also effective in reducingheart Gb3 staining as shown in FIG. 4. The top row of FIG. 4 illustratesVT1 stained heart tissue from Fabry mouse not treated with compound ofFormula 2. The middle three rows of FIG. 4 illustrate heart tissue fromFabry mice that were treated with compound of Formula 2. The bottom rowof FIG. 4 illustrates VT1 staining of heart tissue from normal mice. Theright most column of panels of FIG. 4 are VT1 staining withouthematoxylin/cosin counterstain.

Example #3 Treatment of Fabry Mice with ERT and Compound of Formula 2

Adult Fabry mice are treated intraperitoneally (i.p.) with a bolusinjection of α-galactosidase. Half of the mice are used as controls andthe other half are injected i.p. with the compound of Formula 2. SerumGb3 levels are monitored for nine weeks post ERT (typically in ERT mice,serum Gb3 is undetectable until 9 weeks later, when Gb3 levels arerecovered) at different time points.

Organs (wild-type, Fabry controls, and Fabry treated) are harvested todetermine GSL levels. The GSLs are extracted and levels are determinedby TLC-orcinol, and/or metabolic labeling of GSLs. Serum levels of Gb3may also be determined by VT-1 based ELISA, as Gb3 is the verotoxin (VT)receptor. VT1 staining is typically increased in Fabry mice compared towild-type mice, and effect of treatment with compound 1 on ERT mice canbe determined by VT1 TLC overlay and VT1 staining. Animals treated withthe compound may have lower levels of complex GSLs such as Gb3 andincreased levels of GlcCer and/or LacCer, and decreased VT1 staining ascompared to the controls.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the present invention. It should beunderstood that various alternatives to the embodiments of the presentinvention described herein may be employed in practicing the presentinvention. It is intended that the following claims define the scope ofthe present invention and that methods and structures within the scopeof these claims and their equivalents be covered thereby. The presentinvention is not limited to the embodiments described above, but iscapable of modification within the scope of the appended claims. Thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, many equivalents of the specificembodiments of the present invention described herein.

1. A method for reducing glycolipid synthesis in a subject sufferingfrom a disease other than cancer comprising administering to saidsubject an effective amount of a compound of Formula 1

in the form of a free compound or its pharmaceutically acceptablepro-drug, metabolite, analogue, derivative, solvate or salt wherein thesubstituents R₁, R₂, R₃, and R₄ are defined as described in (a) and (b)below: (a) when R₁ is selected from the group consisting of: (i)substituted C₁₋₁₁ alkyl or substituted C₂₋₁₁ alkenyl, wherein thesubstituents are selected from the group consisting of hydroxy, C₁₋₆alkyloxy; or (ii) mono-, di-, and tri-substituted aryl-C₀₋₁₁ alkylwherein aryl is selected from the group consisting of phenyl, furyl,thienyl wherein the substituents are selected from the group consistingof: (a) phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl,wherein the said phenyl group is mono- or disubstituted with a memberselected from the group consisting of hydroxy, halo, C₁₋₄ alkyl and C₁₋₄alkyloxy, (b) substituted C₁₋₆ alkyl, substituted C₂₋₆ alkyloxy,substituted C₂₋₆ alkylthio, substituted C₂₋₄ alkoxycarbonyl, wherein thesubstituents are selected from the group consisting of C₁₋₆ alkoxy, andC₁₋₆ alkylthio; and (c) C₁₋₁₁ CO₂R₅, C₁₋₁₁CONHR₅, trans-CH═CHCO₂R₅, ortrans-CH═CHCONHR₅ wherein R₅ is C₁₋₁₁ alkyl, or phenyl C₁₋₁₁ alkyl, C₁₋₆alkoxycarbonylmethyleneoxy; then R₂ and R₃ are each independentlyselected from the group consisting of mono-, di, and tri-substitutedphenyl wherein the substituents are independently selected from: (i)substituted C₁₋₆; alkyl, (ii) substituted C₁₋₆ alkyloxy, C₃₋₆alkenyloxy, substituted C₃₋₆ alkenyloxy, (iii) substituted C₁₋₆alkyl-amino, di(substituted C₁₋₆ alkyl)amino, (iv) C₃₋₆ alkenyl-amino,di(C₃₋₆ alkenyl)amino, substituted C₃₋₆ alkenyl-amino, di(substitutedC₃₋₆ alkenyl)amino, (v) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino, whereinthe substituents are selected from the group consisting of: (a) hydroxy,C₁₋₆ alkylalkoxy, C₁₋₆ alkylamino (b) C₃₋₆ alkenyloxy, C₃₋₆alkenylamino, or (c) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆-alkylamino C₃₋₆ alkenyl)piperazino, or R₂and R₃ taken together forming an aryl group or substituted aryl, whereinthe substituents are defined as above in (i)-(v); and R₄ is selectedfrom the group consisting of: (i) hydrogen; (ii) substituted C₁₋₁₁ alkylor C₂₋₁₁ alkenyl wherein the substituents are independently selectedfrom the group consisting of hydrogen, hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio, C₁₋₆ alkylamino, phenyl-C₁₋₆ alkylamino, C₁₋₆ alkoxycarbonyl;or (iii) substituted aryl C₀₋₁₁ alkyl wherein the aryl group is selectedfrom phenyl, imidazolyl, furyl, thienyl in which the substituents areselected from A(a-c); or (b) when R₁ is selected from the groupconsisting of: Mono-, di-, and tri-substituted aryl-C₀₋₆ alkyl whereinaryl is selected from the group consisting of phenyl, thienyl, and thesubstituents are selected from the group consisting of: (a)trans-2-substituted benzimidazolylethenyl, trans-2-substitutedbenzoxazolylethenyl, trans-2-substituted benzthiazolylethenyl, in whichthe substituents are selected from the group consisting of hydrogen,hydroxy, halo, trihalomethyl, C₁₋₄ alkyl and C₁₋₄ alkyloxy, C₁₋₄alkyloxycarbonyl, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₃₋₆alkenylamino, di(C₃₋₆ alkenyl)amino, C₁₋₄ alkyloxy-C₁₋₄ alkylamino,substituted C₁₋₄ alkyl and C₁₋₄ alkyloxy, substituted C₁₋₄alkyloxycarbonyl, substituted C₁₋₄ alkylamino, di(substituted C₁₋₄alkyl)amino, substituted C₃₋₆ alkenylamino, di(substituted C₃₋₆alkenyl)amino, wherein the substituents are as defined above, (b)trans-2-cyano ethenyl, trans-2-alkylsulfonyl ethenyl,trans-2-alkenylsulfonyl ethenyl, trans-2-substituted alkylsulfonylethenyl, trans-2-substituted alkenylsulfonyl ethenyl, in which thesubstituents are defined above, (c) C₁₋₆ CO₂R₅, trans-CH═CHCO₂R₅,C₁₋₆CONHR₅, or trans-CH═CHCONHR₅, wherein R₅ is C₁₋₆ alkoxy C₂₋₆ alkyl,amino C₂₋₆ alkyl, C₁₋₆ alkylamino C₂₋₆ alkyl, di(C₁₋₆ alkyl)amino C₂₋₆alkyl, C₁₋₆ alkylthio C₂₋₆ alkyl, substituted C₁₋₆ alkoxy C₂₋₆ alkyl,substituted C₁₋₆ alkylamino C₂₋₆ alkyl, di(substituted C₁₋₆ alkyl)aminoC₂₋₆ alkyl, substituted C₁₋₄ alkylthio C₂₋₆ alkyl, in which thesubstituents are selected from the group consisting of pyrrolidino,piperidino morpholino, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino,imidazolyl, oxazolyl, thiazolyl, (d) C₁₋₆CONR₆R₇, or trans-CH═CHCONR₆R₇,wherein R₆ and R₇ are independently selected from the group consistingof C₁₋₆ alkyl, phenyl C₁₋₆ alkyl, C₁₋₆ alkoxycarbonylmethyleneoxy,hydroxy C₂₋₆ alkyl, C₁₋₆ alkyloxy C₂₋₆ alkyl, amino C₂₋₆ alkyl, C₁₋₆alkylamino C₂₋₆ alkyl, di(C₁₋₆ alkyl)amino C₂₋₆ alkyl, C₁₋₆ alkylthioC₂₋₆ alkyl, substituted C₁₋₆ alkoxy C₂₋₆ alkyl, substituted C₁₋₆alkylamino C₂₋₆ alkyl, di(substituted C₁₋₆ alkyl)amino C₂₋₆ alkyl,substituted C₁₋₆ alkylthio C₂₋₆ alkyl, wherein the substituents areselected from the group consisting of pyrrolidino, piperidino,morpholino, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino,imidazolyl, oxazolyl, thiazolyl, (e) R₇ C(O)C₁₋₆ alkyl, R₇ C(O)C₂₋₆alkenyl, in which R₇ is defined as above [2(d)], (f) HO—C₁₋₆ alkyl-C₂₋₆alkenyl, R₇—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₆R₇N—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆alkenyl, R₇—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, wherein R₆ and R₇ is definedas above [2(d)], (g) R₇—O—CO 3 alkyl-C₃₋₆ cycloalkan-1-yl, R₇NH—C₀₋₃alkyl-C₃₋₆ cycloalkan-1-yl, R₆R₇N—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl,R₇NH—C(O)—O—C₀₋₃ C₃₋₆ cycloalkan-1-yl, R₆R₇N—C(O)—O—C₀₋₃ alkyl-C₃₋₆cycloalkan-1-yl, R₇O—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl,R₇—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl, R₇O—C(O)—Co-3 alkyl-C₃₋₆cycloalkan-1-yl, wherein R₇ and is defined as above [B(d)]; then R₂ andR₃ are each independently selected from the group consisting of: (1)hydrogen, halo, trihalomethyl, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₂₋₆alkenyl, substituted C₁₋₆ alkenyl, C₁₋₆ alkyloxy, substituted C₁₋₆alkyloxy, C₃₋₆ alkenyloxy, substituted C₃₋₆ alkenyloxy, C₁₋₆ alkylamino,substituted C₁₋₆ alkylamino, C₃₋₆ alkenylamino, substituted C₃₋₆alkenylamino, (2) mono-, di-, and tri-substituted phenyl wherein thesubstituents are independently selected from: (i) halo, trifluoromethyl,substituted C₁₋₆ alkyl, (ii) C₁₋₆ alkyloxy, substituted C₁₋₆ alkyloxy,C₃₋₆ alkenyloxy, substituted C₃₋₆ alkenyloxy, (iii) C₁₋₆ alkyl-amino,di(C₁₋₆ alkyl)amino, substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆alkyl)amino, C₃₋₆ alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆alkenyl-amino, di(substituted C₃₋₆ alkenyl)amino, or (iv) pyrrolidino,piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino,4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxyC₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino,4-N—(C₁₋₆ alkylamino C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino, wherein the substituents are selected from the groupconsisting of: (a) hydrogen, hydroxy, halo, trifluoromethyl, (b) C₁₋₆alkylalkoxy, C₁₋₆ alkylamino, C₁₋₆ alkylthio, (c) C₃₋₆ alkenyloxy, C₃₋₆alkenylamino, C₃₋₆ alkenylthio, or (d) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N—C₁₋₆alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆alkyamino C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino; with the proviso that at least one of R₂ and R₃group be selected from [B (2)] and the phenyl and the substituents beselected from (ii)-(v) above; or R₂ and R₃ taken together forming anaryl group such as phenyl, pyridyl, in which the aryl may be optionallysubstituted, wherein the substituents are defined as above in (i)-(iv);and R₄ is selected from the group consisting of: (a) hydrogen; (b)substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the substituents areindependently selected from the group consisting of: (i) hydrogen,hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio, C₁₋₆ alkylamino, phenyl-C₁₋₆alkylamino, C₁₋₆ alkoxycarbonyl; (ii) substituted C₁₋₆ alkyloxy, C₃₋₆alkenyloxy, substituted C₃₋₆ alkenyloxy, (iii) di(C₁₋₆ alkyl)amino,substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆ alkyl)amino, C₃₋₆alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆ alkenyl-amino,di(substituted C₃₋₆ alkenyl)amino; and (iv) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N—C₁₋₆alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₄ alkoxy C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆alkylamino C₁₋₆ alkyl)piperazino, and 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino; and (c) aryl C₀₋₁₁ alkyl wherein the aryl group isselected from phenyl, imidazolyl, furyl, thienyl.
 2. A method forreducing glycolipid synthesis in a subject suffering from a diseaseother than cancer comprising administering to said subject an effectiveamount of a compound of Formula 1a:

in the form of a free compound or its pharmaceutically acceptablepro-drug, metabolite, analogue, derivative, solvate or salt wherein thesubstituents R₁, R₂, R₃, and R₄ are defined as in A or B: (A) R₁ isselected from the group consisting of: (i) substituted C₁₋₁₁ alkyl orsubstituted C₂₋₁₁ alkenyl, wherein the substituents are selected fromthe group consisting of hydroxy and C₁₋₆ alkyloxy; and (ii) mono-, di-,or tri-substituted aryl-C₀₋₁₁ alkyl wherein aryl is selected from thegroup consisting of phenyl, furyl, and thienyl wherein the substituentsare selected from the group consisting of: (a) phenyltrans-2-phenylethenyl, 2-phenylethynyl, or 2-phenylethyl, wherein thephenyl group is mono- or disubstituted wherein the substituents areselected from the group consisting of hydroxy, halo, C₁₋₄ alkyl and C₁₋₄alkyloxy; (b) substituted C₁₋₆alkyl, substituted C₂₋₆ alkyloxy,substituted C₂₋₆ alkylthio, or substituted C₂₋₆ alkoxycarbonyl, whereinthe substituents are selected from the group consisting of C₁₋₆ alkoxy,and C₁₋₆ alkylthio; and (c) C₁₋₁₁ CO₂R₅, C₁₋₁₁CONHR₅, trans-CH═CHCO₂R₅,or trans-CH═CHCONHR₅ wherein R₅ is C₁₋₁₁ alkyl, phenyl C₁₋₁₁ alkyl, orC₁₋₆ alkoxycarbonylmethyleneoxy; R₂ and R₃ are each independentlyselected from the group consisting of mono-, di, and tri-substitutedphenyl wherein the substituents are independently selected from: (i)substituted C₁₋₆ alkyl; (ii) substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy,or substituted C₃₋₆ alkenyloxy; (iii) substituted C₁₋₆ alkyl-amino,di(substituted C₁₋₆ alkyl)amino; (iv) C₃₋₆ alkenyl-amino, di(C₃₋₆alkenyl)amino, substituted C₃₋₆ alkenyl-amino, or di(substituted C₃₋₆alkenyl)amino; and (v) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy-C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆ alkenyl)piperazino;wherein the substituents for (i), (ii), (iii), (iv), and (iv) areselected from the group consisting of: (a) hydroxy, C₁₋₆ alkoxy, or C₁₋₆alkylamino; (b) C₃₋₆ alkenyloxy, or C₃₋₆ alkenylamino; and (c)pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl,piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino,4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆ alkyl)piperazino, or4-N—(C₁₋₆ alkylamino-C₃₋₆ alkenylpiperazino; or R₂ and R₃ are takentogether to form an aryl group or substituted aryl, wherein thesubstituents are defined as above in (i)-(v); and R₄ is selected fromthe group consisting of: (i) hydrogen; (ii) substituted C₁₋₁₁ alkyl orC₂₋₁₁ alkenyl wherein the substituents are independently selected fromthe group consisting of hydrogen, hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio, C₁₋₆ alkylamino, phenyl-C₁₋₆ alkylamino, and C₁₋₆alkoxycarbonyl; and (iii) substituted aryl C₀₋₁₁ alkyl wherein the arylgroup is selected from phenyl, imidazolyl, furyl, and thienyl in whichthe substituents are selected from the group consisting of: (a) hydroxy,C₁₋₆ alkoxy, or C₁₋₆ alkylamino; (b) C₃₋₆ alkenyloxy, or C₃₋₆alkenylamino; and (c) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆ alkenylpiperazino; or (B)R₁ is selected from the group consisting of: mono-, di-, andtri-substituted aryl-C₀₋₆ alkyl wherein aryl is selected from the groupconsisting of phenyl and thienyl, and the substituents are selected fromthe group consisting of: (i) trans-2-substituted benzimidazolylethenyl,trans-2-substituted benzoxazolylethenyl, or trans-2-substitutedbenzthiazolylethenyl, in which the substituents are selected from thegroup consisting of hydrogen, hydroxy, halo, trihalomethyl, C₁₋₄ alkyl,C₁₋₄ alkyloxy, C₁₋₄ alkyloxycarbonyl, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, C₃₋₆ alkenylamino, di(C₃₋₆ alkenyl)amino, C₁₋₄alkyloxy-C₁₋₄ alkylamino, substituted C₁₋₄ alkyl, substituted C₁₋₄alkyloxy, substituted C₁₋₄ alkyloxycarbonyl, substituted C₁₋₄alkylamino, di(substituted C₁₋₄ alkyl)amino, substituted C₃₋₆alkenylamino, and di(substituted C₃₋₆ alkenyl)amino, wherein thesubstituents are selected from the group consisting of: (a) hydroxy,C₁₋₆ alkoxy, or C₁₋₆ alkylamino; (b) C₃₋₆ alkenyloxy, or C₃₋₆alkenylamino; and (c) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆ alkenyl)piperazino; (ii)trans-2-cyano ethenyl, trans-2-alkylsulfonyl ethenyl,trans-2-alkenylsulfonyl ethenyl, trans-2-substituted alkylsulfonylethenyl, and trans-2-substituted alkenylsulfonyl ethenyl, wherein thesubstituents are selected from the group consisting of: (a) hydroxy,C₁₋₆ alkoxy, or C₁₋₆ alkylamino; (b) C₃₋₆ alkenyloxy, or C₃₋₆alkenylamino; and (c) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₄ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆ alkenyl)piperazino; (iii)C₁₋₆ CO₂R₅, trans-CH═CHCO₂R₅, C₁₋₆CONHR₅, or trans-CH═CHCONHR₄, whereinR₅ is C₁₋₆ alkoxy-C₂₋₆ alkyl, amino-C₂₋₆ alkyl, C₁₋₆ alkylamino-C₂₋₆alkyl, di(C₁₋₆ alkyl)amino-C₂₋₆ alkyl, C₁₋₆ alkylthio-C₂₋₆ alkyl,substituted C₁₋₆ alkoxy-C₂₋₆ alkyl, substituted C₁₋₆ alkylamino-C₂₋₆alkyl, di(substituted C₁₋₆ alkyl)amino-C₂₋₆ alkyl, or substituted C₁₋₆alkylthio-C₂₋₆ alkyl, in wherein the substituents are selected from thegroup consisting of pyrrolidino, piperidino morpholino, piperazino,4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆alkoxy-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy-C₃₋₆ alkenyl)piperazino,4-N—(C₁₋₆ alkylamino-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino, imidazolyl, oxazolyl, and thiazolyl; (iv)C₁₋₆CONHR₅, or trans-CH═CHCONR₆R₇, wherein R₆ and R₇ are independentlyselected from the group consisting of C₁₋₆ alkyl, phenyl-C₁₋₆ alkyl,C₁₋₆ alkoxycarbonylmethyleneoxy, hydroxy-C₂₋₆ alkyl, C₁₋₆ alkyloxy-C₂₋₆alkyl, amino-C₂₋₆ alkyl, C₁₋₆ alkylamino-C₂₋₆ alkyl, di(C₁₋₆alkyl)amino-C₂₋₆ alkyl, C₁₋₆ alkylthio-C₂₋₆ alkyl, substituted C₁₋₆alkoxy-C₂₋₆ alkyl, substituted C₁₋₆ alkylamino-C₂₋₆ alkyl,di(substituted C₁₋₆ alkyl)amino-C₂₋₆ alkyl, substituted C₁₋₆alkylthio-C₂₋₆ alkyl, wherein the substituents are selected from thegroup consisting of pyrrolidino, piperidino, morpholino, piperazino,4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxyC₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy-C₃₋₆ alkenylpiperazino,4-N—(C₁₋₆ alkylamino-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₃₋₆alkenyl)piperazino, imidazolyl, oxazolyl, and thiazolyl; (v)R₇—C(O)—C₁₋₆ alkyl or R₇—C(O)—C₂₋₆ alkenyl, wherein R₇ is defined asabove in [B(iv)]; (vi) HO—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇—O—C₁₋₆ alkyl-C₂₋₆alkenyl, R₇NH—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇N—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, or R₇—C(O)—O—C₁₋₆ alkyl-C₂₋₆alkenyl, wherein R₆ and R₇ is defined as above in [B(iv)]; and (vii)R₇—O—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl, R₇NH—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl,R₆R₇N—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl, R₇NH—C(O)—O—C₀₋₃ C₃₋₆cycloalk-1-yl, R₆R₇N—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl,R₇O—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl, R₇—C(O)—O—C₀₋₃ alkyl-C₃₋₆cycloalk-1-yl, R₇O—C(O)—Co-3 alkyl-C₃₋₆ cycloalk-1-yl, wherein R₇ and R₆are defined as above in [B(iv)]; R₂ and R₃ are each independentlyselected from the group consisting of: (viii) hydrogen, halo,trihalomethyl, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₂₋₆ alkenyl,substituted C₂₋₆ alkenyl, C₁₋₆ alkyloxy, substituted C₁₋₆ alkyloxy, C₃₋₆alkenyloxy, substituted C₃₋₆ alkenyloxy, C₁₋₄ alkylamino, substitutedC₁₋₆ alkylamino, C₃₋₆ alkenylamino, or substituted C₃₋₆ alkenylamino;and (ix) mono-, di-, or tri-substituted phenyl wherein the substituentsare independently selected from the group consisting of: (a) halo,trifluoromethyl, or substituted C₁₋₆ alkyl; (b) C₁₋₆ alkyloxy,substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy, substituted C₃₋₆ alkenyloxy;(c) C₁₋₆ alkyl-amino, di(C₁₋₆ alkyl)amino, substituted C₁₋₆ alkyl-amino,di(substituted C₁₋₆ alkyl)amino, C₃₋₆ alkenyl-amino, di(C₃₋₆alkenyl)amino, substituted C₃₋₆ alkenyl-amino, or di(substituted C₃₋₆alkenyl)amino; and (d) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino;wherein the substituents for (a), (b), (c), and (d) are selected fromthe group consisting of: (1) hydrogen, hydroxy, halo, ortrifluoromethyl; (2) C₁₋₆ alkylalkoxy, C₁₋₆ alkylamino, or C₁₋₆alkylthio; (3) C₃₋₆ alkenyloxy, C₃₋₆ alkenylamino, or C₃₋₆ alkenylthio;and (4) pyrrolidino, piperidino, morpholino, imidazolyl, substitutedimidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino; withthe proviso that a) at least one of R₂ and R₃ is selected from [B (ix)]and wherein the substituents are selected from [B (ix) (b)-(d)] above;or b) R₂ and R₃ are taken together to form an optionally substitutedaryl group, wherein the substituents are defined as above in [B (ix)(a)-(d)]; and R₄ is selected from the group consisting of: (i) hydrogen;(ii) substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the substituentsare independently selected from the group consisting of: (a) hydrogen,hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio, C₁₋₆ alkylamino, phenyl-C₁₋₆alkylamino, or C₁₋₆ alkoxycarbonyl; (b) substituted C₁₋₆ alkyloxy, C₃₋₆alkenyloxy, or substituted C₃₋₆ alkenyloxy; (c) di(C₁₋₆ alkyl)amino,substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆ alkyl)amino, C₃₋₆alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆ alkenyl-amino, ordi(substituted C₃₋₆ alkenyl)amino; and (d) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N—C₁₋₆alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆alkylamino C₁₋₆ alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino; and (iii) aryl C₀₋₁₁ alkyl wherein the aryl group isselected from phenyl, imidazolyl, furyl, or thienyl.
 3. A method fortreating a lipid storage disease in a subject comprising administeringto said subject an effective amount of a compound of Formula 1

in the form of a free compound or its pharmaceutically acceptablepro-drug, metabolite, analogue, derivative, solvate or salt wherein thesubstituents R₁, R₂, R₃, and R₄ are defined as described in A and Bbelow: (a) when R₁ is selected from the group consisting of: (i)substituted C₁₋₁₁ alkyl or substituted C₂₋₁₁ alkenyl, wherein thesubstituents are selected from the group consisting of hydroxy, C₁₋₆alkyloxy; or (ii) mono-, di-, and tri-substituted aryl-C₀₋₁₁ alkylwherein aryl is selected from the group consisting of phenyl, furyl,thienyl wherein the substituents are selected from the group consistingof: (a) phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl,wherein the said phenyl group is mono- or disubstituted with a memberselected from the group consisting of hydroxy, halo, C₁₋₄ alkyl and C₁₋₄alkyloxy, (b) substituted C₁₋₆ alkyl, substituted C₂₋₆ alkyloxy,substituted C₂₋₄ alkylthio, substituted C₂₋₆ alkoxycarbonyl, wherein thesubstituents are selected from the group consisting of C₁₋₆ alkoxy, andC₁₋₆ alkylthio; and (c) C₁₋₁₁ CO₂R₅, C₁₋₁₁ CONHR₅, trans-CH═CHCO₂R₅, ortrans-CH═CHCONHR₅ wherein R₅ is C₁₋₁₁ alkyl, or phenyl C₁₋₁₁ alkyl, C₁₋₆alkoxycarbonylmethyleneoxy; then R₂ and R₃ are each independentlyselected from the group consisting of mono-, di, and tri-substitutedphenyl wherein the substituents are independently selected from: (i)substituted C₁₋₆ alkyl, (ii) substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy,substituted C₃₋₆ alkenyloxy, (iii) substituted C₁₋₆ alkyl-amino,di(substituted C₁₋₆ alkyl)amino, (iv) C₃₋₆ alkenyl-amino, di(C₃₋₆alkenyl)amino, substituted C₃₋₆ alkenyl-amino, di(substituted C₃₋₆alkenyl)amino, (v) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino, whereinthe substituents are selected from the group consisting of: (a) hydroxy,C₁₋₆ alkylalkoxy, C₁₋₆ alkylamino (b) C₃₋₆ alkenyloxy, C3-6alkenylamino, or (c) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino, or R₂and R₃ taken together forming an aryl group or substituted aryl, whereinthe substituents are defined as above in (i)-(v); and R₄ is selectedfrom the group consisting of: (i) hydrogen; (ii) substituted C₁₋₁₁ alkylor C₂₋₁₁ alkenyl wherein the substituents are independently selectedfrom the group consisting of hydrogen, hydroxy, C₁₋₆ alkyloxy,C₁₋₆alkylthio, C₁₋₆ alkylamino, phenyl-C₁₋₆ alkylamino, C₁₋₆alkoxycarbonyl; or (iii) substituted aryl C₀₋₁₁ alkyl wherein the arylgroup is selected from phenyl, imidazolyl, furyl, thienyl in which thesubstituents are selected from A(a-c); or (b) when R₁ is selected fromthe group consisting of: Mono-, di-, and tri-substituted aryl-C₀₋₆ alkylwherein aryl is selected from the group consisting of phenyl, thienyl,and the substituents are selected from the group consisting of: (a)trans-2-substituted benzimidazolylethenyl, trans-2-substitutedbenzoxazolylethenyl, trans-2-substituted benzthiazolylethenyl, in whichthe substituents are selected from the group consisting of hydrogen,hydroxy, halo, trihalomethyl, C₁₋₄ alkyl and C₁₋₄ alkyloxy, C₁₋₄alkyloxycarbonyl, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₃₋₆alkenylamino, di(C₃₋₆ alkenyl)amino, C₁₋₄ alkyloxy-C₁₋₄ alkylamino,substituted C₁₋₄ alkyl and C₁₋₄ alkyloxy, substituted C₁₋₄alkyloxycarbonyl, substituted C₁₋₄ alkylamino, di(substituted C₁₋₄alkyl)amino, substituted C₃₋₆ alkenylamino, di(substituted C₃₋₆alkenyl)amino, wherein the substituents are as defined above, (b)trans-2-cyano ethenyl, trans-2-alkylsulfonyl ethenyl,trans-2-alkenylsulfonyl ethenyl, trans-2-substituted alkylsulfonylethenyl, trans-2-substituted alkenylsulfonyl ethenyl, in which thesubstituents are defined above, (c) C₁₋₆ CO₂R₅, trans-CH═CHCO₂R₅,C₁₋₆CONHR₅, or trans-CH═CHCONHR₅, wherein R₅ is C₁₋₆ alkoxy C₂₋₆ alkyl,amino C₂₋₆ alkyl, C₁₋₆ alkylamino C₂₋₆ alkyl, di(C₁₋₆ alkyl)amino C₂₋₆alkyl, C₁₋₆ alkylthio C₂₋₆ alkyl, substituted C₁₋₆ alkoxy C₂₋₆ alkyl,substituted C₁₋₆ alkylamino C₂₋₆ alkyl, di(substituted C₁₋₆ alkyl)aminoC₂₋₆ alkyl, substituted C₁₋₆ alkylthio C₂₋₆ alkyl, in which thesubstituents are selected from the group consisting of pyrrolidino,piperidino morpholino, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino,imidazolyl, oxazolyl, thiazolyl, (d) C₁₋₆CONR₆R₇, or trans-CH═CHCONR₆R₇,wherein R₆ and R₇ are independently selected from the group consistingof C₁₋₆ alkyl, phenyl C₁₋₆ alkyl, C₁₋₆ alkoxycarbonylmethyleneoxy,hydroxy C₂₋₆ alkyl, C₁₋₆ alkyloxy C₂₋₆ alkyl, amino C₂₋₆ alkyl, C₁₋₆alkylamino C₂₋₆ alkyl, di(C₁₋₆ alkyl)amino C₂₋₆ alkyl, C₁₋₆ alkylthioC₂₋₆ alkyl, substituted C₁₋₆ alkoxy C₂₋₆ alkyl, substituted C₁₋₆alkylamino C₂₋₆ alkyl, di(substituted C₁₋₆ alkyl)amino C₂₋₆ alkyl,substituted C₁₋₆ alkylthio C₂₋₆ alkyl, wherein the substituents areselected from the group consisting of pyrrolidino, piperidino,morpholino, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C 6 alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino,imidazolyl, oxazolyl, thiazolyl, (e) R₇ C(O) C₁₋₆ alkyl, R₇ C(O)C₂₋₆alkenyl, in which R₇ is defined as above [2(d)], (f) HO—C₁₋₆ alkyl-C₂₋₆alkenyl, R₇—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH—C₁₋₄ alkyl-C₂₋₆ alkenyl,R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₆R₇N—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆alkenyl, R₇—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, wherein R₆ and R₇ is definedas above [2(d)], (g) R₇—O—C₁₋₃ alkyl-C₃₋₆ cycloalkan-1-yl, R₇NH—C₀₋₃alkyl-C₃₋₆ cycloalkan-1-yl, R₆R₇N—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl,R₇NH—C(O)—O—C₀₋₃ C₃₋₆ cycloalkan-1-yl, R₆R₇N—C(O)—O—C₀₋₃ alkyl-C₃₋₆cycloalkan-1-yl, R₇O—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl,R₇—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl, R₇O—C(O)—C₀₋₃ alkyl-C₃₋₆cycloalkan-1-yl, wherein R₇ and is defined as above [B(d)]; then R₂ andR₃ are each independently selected from the group consisting of: (1)hydrogen, halo, trihalomethyl, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₂₋₆alkenyl, substituted C₁₋₆ alkenyl, C₁₋₆ alkyloxy, substituted C₁₋₆alkyloxy, C₃₋₆ alkenyloxy, substituted C₃₋₆ alkenyloxy, C₁₋₆ alkylamino,substituted C₁₋₆ alkylamino, C₃₋₆ alkenylamino, substituted C₃₋₆alkenylamino, (2) mono-, di-, and tri-substituted phenyl wherein thesubstituents are independently selected from: (i) halo, trifluoromethyl,substituted C₁₋₆ alkyl, (ii) C₁₋₆ alkyloxy, substituted C₁₋₆ alkyloxy,C₃₋₆ alkenyloxy, substituted C₃₋₆ alkenyloxy, (iii) C₁₋₆ alkyl-amino,di(C₁₋₆ alkyl)amino, substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆alkyl)amino, C₃₋₆ alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆alkenyl-amino, di(substituted C₃₋₆ alkenyl)amino, or (iv) pyrrolidino,piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino,4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxyC₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino,4-N—(C₁₋₆ alkylamino C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino, wherein the substituents are selected from the groupconsisting of: (a) hydrogen, hydroxy, halo, trifluoromethyl, (b) C₁₋₆alkylalkoxy, C₁₋₆ alkylamino, C₁₋₆ alkylthio, (c) C₃₋₆ alkenyloxy, C₃₋₆alkenylamino, C₃₋₆ alkenylthio, or (d) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imdazolyl, piperazino, 4-N—C₁₋₆alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆alkylamino C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino; with the proviso that at least one of R₂ and R₃group be selected from [B (2)] and the phenyl and the substituents beselected from (ii)-(v) above; or R₂ and R₃ taken together forming anaryl group such as phenyl, pyridyl, in which the aryl may be optionallysubstituted, wherein the substituents are defined as above in (i)-(iv);and R₄ is selected from the group consisting of: (a) hydrogen; (b)substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the substituents areindependently selected from the group consisting of: (i) hydrogen,hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio, C₁₋₆ alkylamino, phenyl-C₁₋₆alkylamino, C₁₋₆ alkoxycarbonyl; (ii) substituted C₁₋₆ alkyloxy, C₃₋₆alkenyloxy, substituted C₃₋₆ alkenyloxy, (iii) di(C₁₋₆ alkyl)amino,substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆ alkyl)amino, C₃₋₆alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆ alkenyl-amino,di(substituted C₃₋₆ alkenyl)amino; and (iv) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N—C₁₋₆alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆alkylamino C₁₋₆ alkyl)piperazino, and 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino; and (c) aryl C₀₋₁₁ alkyl wherein the aryl group isselected from phenyl, imidazolyl, furyl, thienyl.
 4. A method fortreating a lipid storage disease in a subject comprising administeringto said subject an effective amount of a compound of Formula 1a:

in the form of a free compound or its pharmaceutically acceptablepro-drug, metabolite, analogue, derivative, solvate or salt wherein thesubstituents R₁, R₂, R₃, and R₄ are defined as described in A and Bbelow: (A) R₁ is selected from the group consisting of: (i) substitutedC₁₋₁₁ alkyl or substituted C₂₋₁₁ alkenyl, wherein the substituents areselected from the group consisting of hydroxy and C₁₋₆ alkyloxy; and(ii) mono-, di-, or tri-substituted aryl-C₀₋₁₁ alkyl wherein aryl isselected from the group consisting of phenyl, furyl, and thienyl whereinthe substituents are selected from the group consisting of: (a) phenyl,trans-2-phenylethenyl, 2-phenylethynyl, or 2-phenylethyl, wherein thephenyl group is mono- or disubstituted wherein the substituents areselected from the group consisting of hydroxy, halo, C₁₋₄ alkyl and C₁₋₄alkyloxy; (b) substituted C₁₋₆ alkyl, substituted C₂₋₆ alkyloxy,substituted C₂₋₆ alkylthio, or substituted C₂₋₆ alkoxycarbonyl, whereinthe substituents are selected from the group consisting of C₁₋₆ alkoxy,and C₁₋₆ alkylthio; and (c) C₁₋₁₁ CO₂R₅, C₁₋₁₁CONHR₅, trans-CH═CHCO₂R₅,or trans-CH═CHCONHR₅ wherein R₅ is C₁₋₁₁ alkyl, phenyl C₁₋₁₁ alkyl, orC₁₋₆ alkoxycarbonylmethyleneoxy; R₂ and R₃ are each independentlyselected from the group consisting of mono-, di, and tri-substitutedphenyl wherein the substituents are independently selected from: (i)substituted C₁₋₆ alkyl; (ii) substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy,or substituted C₃₋₆ alkenyloxy; (iii) substituted C₁₋₆ alkyl-amino,di(substituted C₁₋₆ alkyl)amino; (iv) C₃₋₆ alkenyl-amino, di(C₃₋₆alkenyl)amino, substituted C₃₋₆ alkenyl-amino, or di(substituted C₃₋₆alkenyl)amino; and (v) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N— (C₁₋₆ alkoxy-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy-C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkyl amino-C₃₋₆ alkenyl)piperazino;wherein the substituents for (i), (ii), (iii), (iv), and (v) areselected from the group consisting of: (a) hydroxy, C₁₋₆ alkoxy, or C₁₋₆alkylamino; (b) C₃₋₆ alkenyloxy, or C₃₋₆ alkenylamino; and (c)pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl,piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino,4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆ alkyl)piperazino, or4-N—(C₁₋₆ alkylamino-C₃₋₆ alkenyl)piperazino; or R₂ and R₃ are takentogether to form an aryl group or substituted aryl, wherein thesubstituents are defined as above in (i)-(v); and R₄ is selected fromthe group consisting of: (i) hydrogen; (ii) substituted C₁₋₁₁ alkyl orC₂₋₁₁ alkenyl wherein the substituents are independently selected fromthe group consisting of hydrogen, hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio,C₁₋₆ alkylamino, phenyl-C₁₋₆ alkylamino, and C₁₋₆ alkoxycarbonyl; and(iii) substituted aryl C₀₋₁₁ alkyl wherein the aryl group is selectedfrom phenyl, imidazolyl, furyl, and thienyl in which the substituentsare selected from the group consisting of: (a) hydroxy, C₁₋₆ alkoxy, orC₁₋₆ alkylamino; (b) C₃₋₆ alkenyloxy, or C₃₋₆ alkenylamino; and (c)pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl,piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino,4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆ alkyl)piperazino, or4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino; or (B) R₁ is selected fromthe group consisting of: mono-, di-, and tri-substituted aryl-C₀₋₆ alkylwherein aryl is selected from the group consisting of phenyl andthienyl, and the substituents are selected from the group consisting of:(i) trans-2-substituted benzimidazolylethenyl, trans-2-substitutedbenzoxazolylethenyl, or trans-2-substituted benzthiazolylethenyl, inwhich the substituents are selected from the group consisting ofhydrogen, hydroxy, halo, trihalomethyl, C₁₋₄ alkyl, C₁₋₄ alkyloxy, C₁₋₄alkyloxycarbonyl, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₃₋₆alkenylamino, di(C₃₋₆ alkenyl)amino, C₁₋₄ alkyloxy-C₁₋₄ alkylamino,substituted C₁₋₄ alkyl, substituted C₁₋₄ alkyloxy, substituted C₁₋₄alkyloxycarbonyl, substituted C₁₋₄ alkylamino, di(substituted C₁₋₄alkyl)amino, substituted C₃₋₆ alkenylamino, and di(substituted C₃₋₆alkenyl)amino, wherein the substituents are selected from the groupconsisting of: (a) hydroxy, C₁₋₆ alkoxy, or C₁₋₆ alkylamino; (b) C₃₋₆alkenyloxy, or C₃₋₆ alkenylamino; and (c) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N—C₁₋₆alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆alkylamino-C₁₋₆ alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆alkenyl)piperazino; (ii) trans-2-cyano ethenyl, trans-2-alkylsulfonylethenyl, trans-2-alkenylsulfonyl ethenyl, trans-2-substitutedalkylsulfonyl ethenyl, and trans-2-substituted alkenylsulfonyl ethenyl,wherein the substituents are selected from the group consisting of: (a)hydroxy, C₁₋₆ alkoxy, or C₁₋₆ alkylamino; (b) C₃₋₆ alkenyloxy, or C₃₋₆alkenylamino; and (c) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆ alkenyl)piperazino; (iii)C₁₋₆ CO₂R₅, trans-CH═CHCO₂R₅, C₁₋₆ CONHR₅, or trans-CH═CHCONHR₅, whereinR₅ is C₁₋₆ alkoxy-C₂₋₆ alkyl, amino-C₂₋₆ alkyl, C₁₋₆ alkylamino-C₂₋₆alkyl, di(C₁₋₆ alkyl)amino-C₂₋₆ alkyl, C₁₋₆ alkylthio-C₂₋₆ alkyl,substituted C₁₋₆ alkoxy-C₂₋₆ alkyl, substituted C₁₋₆ alkylamino-C₂₋₆alkyl, di(substituted C₁₋₆ alkyl)amino-C₂₋₆ alkyl, or substituted C₁₋₆alkylthio-C₂₋₆ alkyl, in which the substituents are selected from thegroup consisting of pyrrolidino, piperidino morpholino, piperazino,4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆alkoxy-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy-C₃₋₆ alkenyl)piperazino,4-N—(C₁₋₆ alkylamino-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino, imidazolyl, oxazolyl, and thiazolyl; (iv)C₁₋₆CONHR₅, or trans-CH═CHCONR₆R₇, wherein R₆ and R₇ are independentlyselected from the group consisting of C₁₋₆ alkyl, phenyl-C₁₋₆ alkyl,C₁₋₆ alkoxycarbonylmethyleneoxy, hydroxy-C₂₋₆ alkyl, C₁₋₆ alkyloxy-C₂₋₆alkyl, amino-C₂₋₆ alkyl, C₁₋₆ alkylamino-C₂₋₆ alkyl, di(C₁₋₆alkyl)amino-C₂₋₆ alkyl, C₁₋₆ alkylthio-C₂₋₆ alkyl, substituted C₁₋₆alkoxy-C₂₋₆ alkyl, substituted C₁₋₆ alkylamino-C₂₋₆ alkyl,di(substituted C₁₋₆ alkyl)amino-C₂₋₆ alkyl, substituted C₁₋₆alkylthio-C₂₋₆ alkyl, wherein the substituents are selected from thegroup consisting of pyrrolidino, piperidino, morpholino, piperazino,4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxyC₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy-C₃₋₆ alkenyl)piperazino,4-N—(C₁₋₆ alkylamino-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₃₋₆alkenyl)piperazino, imidazolyl, oxazolyl, and thiazolyl; (v)R₇—C(O)—C₁₋₆ alkyl or R₇—C(O)—C₂₋₆ alkenyl, wherein R₇ is defined asabove in [B(iv)]; (vi) HO—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇—O—C₁₋₆ alkyl-C₂₋₆alkenyl, R₇NH—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C(O)—O—C₁₋₆ alkyl-C₂₋₆alkenyl, R₇O—C(O)—O—C₁₋₄ alkyl-C₂₋₆ alkenyl, or R₇—C(O)—O—C₁₋₆alkyl-C₂₋₆ alkenyl, wherein R₆ and R₇ is defined as above hi [B(iv)];and (vii) R₇—O—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl, R₇NH—C₀₋₃ alkyl-C₃₋₆cycloalk-1-yl, R₆R₇N—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl, R₇NH—C(O)—O—C₀₋₃C₃₋₆ cycloalk-1-yl, R₆R₇N—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl,R₇O—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl, R₇—C(O)—O—C₀₋₃ alkyl-C₃₋₆cycloalk-1-yl, R₇O—C(O)—Co-3 alkyl-C₃₋₆ cycloalk-1-yl, wherein R₇ and R₆are defined as above in [B(iv)]; R₂ and R₃ are each independentlyselected from the group consisting of: (viii) hydrogen, halo,trihalomethyl, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₂₋₆ alkenyl,substituted C₂₋₆ alkenyl, C₁₋₆ alkyloxy, substituted C₁₋₆ alkyloxy, C₃₋₆alkenyloxy, substituted C₃₋₆ alkenyloxy, C₁₋₆ alkylamino, substitutedC₁₋₆ alkylamino, C₃₋₆ alkenylamino, or substituted C₃₋₆ alkenylamino;and (ix) mono-, di-, or tri-substituted phenyl wherein the substituentsare independently selected from the group consisting of: (a) halo,trifluoromethyl, or substituted C₁₋₆ alkyl; (b) C₁₋₆ alkyloxy,substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy, substituted C₃₋₆ alkenyloxy;(c) C₁₋₆ alkyl-amino, di(C₁₋₆ alkyl)amino, substituted C₁₋₆ alkyl-amino,di(substituted C₁₋₆ alkyl)amino, C₃₋₆ alkenyl-amino, di(C₃₋₆alkenyl)amino, substituted C₃₋₆ alkenyl-amino, or di(substituted C₃₋₆alkenyl)amino; and (d) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino;wherein the substituents for (a), (b), (c), and (d) are selected fromthe group consisting of: (1) hydrogen, hydroxy, halo, ortrifluoromethyl; (2) C₁₋₆ alkylalkoxy, C₁₋₆ alkylamino, or C₁₋₆alkylthio; (3) C₃₋₆ alkenyloxy, C₃₋₆ alkenylamino, or C₃₋₆ alkenylthio;and (4) pyrrolidino, piperidino, morpholino, imidazolyl, substitutedimdazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino; withthe proviso that a) at least one of R₂ and R₃ is selected from [B (ix)]and wherein the substituents are selected from [B (ix) (b)-(d)] above;or b) R₂ and R₃ are taken together to form an optionally substitutedaryl group, wherein the substituents are defined as above in [B (ix)(a)-(d)]; and R₄ is selected from the group consisting of: (i) hydrogen;(ii) substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the substituentsare independently selected from the group consisting of: (a) hydrogen,hydroxy, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, C₁₋₆ alkylamino, phenyl-C₁₋₆alkylamino, or C₁₋₆ alkoxycarbonyl; (b) substituted C₁₋₆ alkyloxy, C₃₋₆alkenyloxy, or substituted C₃₋₆ alkenyloxy; (c) di(C₁₋₆ alkyl)amino,substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆ alkyl)amino, C₃₋₆alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆ alkenyl-amino, ordi(substituted C₃₋₆ alkenyl)amino; and (d) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N—C₁₋₆alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆alkylamino C₁₋₆ alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino; and (iii) aryl C₀₋₁₁ alkyl wherein the aryl group isselected from phenyl, imidazolyl, furyl, or thienyl.
 5. The method ofclaim 1, 2, 3, or 4, wherein the compound of Formula 1 has the followingformula (Formula 2):

in the form of a free compound or as its pharmaceutically-acceptablepro-drug, metabolite, analogue, derivative, solvate or salt.
 6. Themethod of claim 3 or 4 wherein the disease is characterized by a defectin glycosphingolipid synthesis.
 7. The method of claim 6, wherein theglycosphingolipid is a neutral glycosphingolipid.
 8. The method of claim3 or 4 wherein the disease is characterized by a defect in ceramidesynthesis.
 9. The method of claim 3 or 4 wherein the disease isGaucher's disease.
 10. The method of claim 3 or 4 wherein the disease isFabry's disease.
 11. The method of claim 3 or 4 wherein the disease ischaracterized by a defect in ganglioside synthesis in the subject. 12.The method of claim 11, wherein the ganglioside is a GM1 ganglioside.13. The method of claim 11, wherein the ganglioside is a GM2ganglioside.
 14. The method of claim 13, wherein the disease is TaySach's disease.
 15. The method of claim 13, wherein the disease isSandhoff's disease.
 16. The method of claim 11, wherein the disease iscystic fibrosis.
 17. A method for treating a lipid storage disease in asubject comprising administering to the subject an effective amount of:a first compound of Formula 1

in the form of a free compound or its pharmaceutically acceptablepro-drug, metabolite, analogue, derivative, solvate or salt wherein thesubstituents R₁, R₂, R₃, and R₄ are defined as described in A and Bbelow: (a) when R₁ is selected from the group consisting of: (i)substituted C₁₋₁₁ alkyl or substituted C₂₋₁₁ alkenyl, wherein thesubstituents are selected from the group consisting of hydroxy, C₁₋₆alkyloxy; or (ii) mono-, di-, and tri-substituted aryl-C₀₋₁₁ alkylwherein aryl is selected from the group consisting of phenyl, furyl,thienyl wherein the substituents are selected from the group consistingof: (a) phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl,wherein the said phenyl group is mono- or disubstituted with a memberselected from the group consisting of hydroxy, halo, C₁₋₄ alkyl and C₁₋₄alkyloxy, (b) substituted C₁₋₆ alkyl, substituted C₂₋₆ alkyloxy,substituted C₂₋₆ alkylthio, substituted C₂₋₆ alkoxycarbonyl, wherein thesubstituents are selected from the group consisting of C₁₋₆ alkoxy, andC₁₋₆alkylthio; and (c) C₁₋₁₁ CO₂R₅, C₁₋₁₁CONHR₅, trans-CH═CHCO₂R₅, ortrans-CH═CHCONHR₅ wherein R₅ is C₁₋₁₁ alkyl, or phenyl C₁₋₁₁ alkyl, C₁₋₆alkoxycarbonylmethyleneoxy; then R₂ and R₃ are each independentlyselected from the group consisting of mono-, di, and tri-substitutedphenyl wherein the substituents are independently selected from: (i)substituted C₁₋₆ alkyl, (ii) substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy,substituted C₃₋₆ alkenyloxy, (iii) substituted C₁₋₆ alkyl-amino,di(substituted C₁₋₆ alkyl)amino, (iv) C₃₋₆ alkenyl-amino, di(C₃₋₆alkenyl)amino, substituted C₃₋₆ alkenyl-amino, di(substituted C₃₋₆alkenyl)amino, (v) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino, whereinthe substituents are selected from the group consisting of: (a) hydroxy,C₁₋₆ alkylalkoxy, C₁₋₆ alkylamino (b) C₃₋₆ alkenyloxy, C₃₋₆alkenylamino, or (c) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino,4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino, or R₂and R₃ taken together forming an aryl group or substituted aryl, whereinthe substituents are defined as above in (i)-(v); and R₄ is selectedfrom the group consisting of: (i) hydrogen; (ii) substituted C₁₋₁₁ alkylor C₂₋₁₁ alkenyl wherein the substituents are independently selectedfrom the group consisting of hydrogen, hydroxy, C₁₋₆ alkyloxy,C₁₋₆alkylthio, C₁₋₆ alkylamino, phenyl-C₁₋₆ alkylamino, C₁₋₆alkoxycarbonyl; or (iii) substituted aryl C₀₋₁₁ alkyl wherein the arylgroup is selected from phenyl, imidazolyl, furyl, thienyl in which thesubstituents are selected from A(a-c); or (b) when R₁ is selected fromthe group consisting of: Mono-, di-, and tri-substituted aryl-C₀₋₆ alkylwherein aryl is selected from the group consisting of phenyl, thienyl,and the substituents are selected from the group consisting of: (a)trans-2-substituted benzimidazolylethenyl, trans-2-substitutedbenzoxazolylethenyl, trans-2-substituted benzthiazolylethenyl, in whichthe substituents are selected from the group consisting of hydrogen,hydroxy, halo, trihalomethyl, C₁₋₄ alkyl and C₁₋₄ alkyloxy, C₁₋₄alkyloxycarbonyl, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₃₋₆alkenylamino, di(C₃₋₆ alkenyl)amino, C₁₋₄ alkyloxy-C₁₋₄ alkylamino,substituted C₁₋₄ alkyl and C₁₋₄ alkyloxy, substituted C₁₋₄alkyloxycarbonyl, substituted C₁₋₄ alkylamino, di(substituted C₁₋₄alkyl)amino, substituted C₃₋₆ alkenylamino, di(substituted C₃₋₆alkenyl)amino, wherein the substituents are as defined above, (b)trans-2-cyano ethenyl, trans-2-alkylsulfonyl ethenyl,trans-2-alkenylsulfonyl ethenyl, trans-2-substituted alkylsulfonylethenyl, trans-2-substituted alkenylsulfonyl ethenyl, in which thesubstituents are defined above, (c) C₁₋₆ CO₂R₅, trans-CH═CHCO₂R₅,C₁₋₆CONHR₅, or trans-CH═CHCONHR₅, wherein R₅ is C₁₋₆ alkoxy C₂₋₆ alkyl,amino C₂₋₆ alkyl, C₁₋₆ alkylamino C₂₋₆ alkyl, di(C₁₋₆ alkyl)amino C₂₋₆alkyl, C₁₋₄ alkylthio C₂₋₆ alkyl, substituted C₁₋₆ alkoxy C₂₋₆ alkyl,substituted C₁₋₆ alkylamino C₂₋₆ alkyl, di(substituted C₁₋₆ alkyl)aminoC₂₋₆ alkyl, substituted C₁₋₆ alkylthio C₂₋₆ alkyl, in which thesubstituents are selected from the group consisting of pyrrolidino,piperidino morpholino, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino,imidazolyl, oxazolyl, thiazolyl, (d) C₁₋₆CONR₆R₇, or trans-CH═CHCONR₆R₇,wherein R₅ and R₇ are independently selected from the group consistingof C₁₋₆ alkyl, phenyl C₁₋₆ alkyl, C₁₋₆ alkoxycarbonylmethyleneoxy,hydroxy C₂₋₆ alkyl, C₁₋₆ alkyloxy C₂₋₆ alkyl, amino C₂₋₆ alkyl, C₁₋₆alkylamino C₂₋₆ alkyl, di(C₁₋₆ alkyl)amino C₂₋₆ alkyl, C₁₋₆ alkylthioC₂₋₆ alkyl, substituted C₁₋₆ alkoxy C₂₋₆ alkyl, substituted C₁₋₆alkylamino C₂₋₆ alkyl, di(substituted C₁₋₆ alkyl)amino C₂₋₆ alkyl,substituted C₁₋₆ alkylthio C₂₋₆ alkyl, wherein the substituents areselected from the group consisting of pyrrolidino, piperidino,morpholino, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino,imidazolyl, oxazolyl, thiazolyl, (e) R₇ C(O)C₁₋₆ alkyl, R₇ C(O)C₂₋₆alkenyl, in which R₇ is defined as above [2(d)], (f) HO—C₁₋₆ alkyl-C₂₋₆alkenyl, R₇—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₆R₇N—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆alkenyl, R₇—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, wherein R₆ and R₇ is definedas above [2(d)], (g) R₇—O—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl, R₇NH—C₀₋₃alkyl-C₃₋₆ cycloalkan-1-yl, R₆R₇N—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl,R₇NH—C(O)—O—C₀₋₃ C₃₋₆ cycloalkan-1-yl, R₆R₇N—C(O)—O—C₀₋₃ alkyl-C₃₋₆cycloalkan-1-yl, R₇O—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl,R₇—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl, R₇O—C(O)—Co-3 alkyl-C₃₋₆cycloalkan-1-yl, wherein R₇ and is defined as above [B(d)]; then R₂ andR₃ are each independently selected from the group consisting of: (1)hydrogen, halo, trihalomethyl, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₂₋₆alkenyl, substituted C₁₋₆ alkenyl, C₁₋₆ alkyloxy, substituted C₁₋₆alkyloxy, C₃₋₆ alkenyloxy, substituted C₃₋₆ alkenyloxy, C₁₋₆ alkylamino,substituted C₁₋₆ alkylamino, C₃₋₆ alkenylamino, substituted C₃₋₆alkenylamino, (2) mono-, di-, and tri-substituted phenyl wherein thesubstituents are independently selected from: (i) halo, trifluoromethyl,substituted C₁₋₆ alkyl, (ii) C₁₋₆ alkyloxy, substituted C₁₋₆ alkyloxy,C₃₋₆ alkenyloxy, substituted C₃₋₆ alkenyloxy, (iii) C₁₋₆ alkyl-amino,di(C₁₋₆ alkyl)amino, substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆alkyl)amino, C₃₋₆ alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆alkenyl-amino, di(substituted C₃₋₆ alkenyl)amino, or (iv) pyrrolidino,piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino,4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxyC₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino,4-N—(C₁₋₆ alkylamino C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino, wherein the substituents are selected from the groupconsisting of: (a) hydrogen, hydroxy, halo, trifluoromethyl, (b) C₁₋₆alkylalkoxy, C₁₋₆ alkylamino, C₁₋₆ alkylthio, (c) C₃₋₆ alkenyloxy, C₃₋₆alkenylamino, C₃₋₆ alkenylthio, or (d) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N—C₁₋₆alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆alkylamino C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino; with the proviso that at least one of R₂ and R₃group be selected from [B (2)] and the phenyl and the substituents beselected from (ii)-(v) above; or R₂ and R₃ taken together forming anaryl group such as phenyl, pyridyl, in which the aryl may be optionallysubstituted, wherein the substituents are defined as above in (i)-(iv);and R₄ is selected from the group consisting of: (a) hydrogen; (b)substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the substituents areindependently selected from the group consisting of: (i) hydrogen,hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio, C₁₋₆ alkylamino, phenyl-C₁₋₆alkylamino, C₁₋₆ alkoxycarbonyl; (ii) substituted C₁₋₆ alkyloxy, C₃₋₆alkenyloxy, substituted C₃₋₆ alkenyloxy, (iii) di(C₁₋₆ alkyl)amino,substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆ alkyl)amino, C₃₋₆alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆ alkenyl-amino,di(substituted C₃₋₆ alkenyl)amino; and (iv) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N—C₁₋₆alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆alkylamino C₁₋₆ alkyl)piperazino, and 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino; and (c) aryl C₀₋₁₁ alkyl wherein the aryl group isselected from phenyl, imidazolyl, furyl, thienyl; and a second compoundeffective to treat the lipid storage disease.
 18. A method for treatinga lipid storage disease in a subject comprising administering to thesubject an effective amount of: a first compound of Formula 1a:

in the form of a free compound or its pharmaceutically acceptablepro-drug, metabolite, analogue, derivative, solvate or salt wherein thesubstituents R₁, R₂, R₃, and R₄ are defined as described in A and Bbelow: (A) R₁ is selected from the group consisting of: (i) substitutedC₁₋₁₁ alkyl or substituted C₂₋₁₁ alkenyl, wherein the substituents areselected from the group consisting of hydroxy and C₁₋₆ alkyloxy; and(ii) mono-, di-, or tri-substituted aryl-C₀₋₁₁ alkyl wherein aryl isselected from the group consisting of phenyl, furyl, and thienyl whereinthe substituents are selected from the group consisting of: (a) phenyl,trans-2-phenylethenyl, 2-phenylethynyl, or 2-phenylethyl, wherein thephenyl group is mono- or disubstituted wherein the substituents areselected from the group consisting of hydroxy, halo, C₁₋₄ alkyl and C₁₋₄alkyloxy; (b) substituted C₁₋₆ alkyl, substituted C₂₋₆ alkyloxy,substituted C₂₋₆ alkylthio, or substituted C₂₋₆ alkoxycarbonyl, whereinthe substituents are selected from the group consisting of C₁₋₆ alkoxy,and C₁₋₆ alkylthio; and (c) C₁₋₁₁ CO₂R₅, C₁₋₁₁CONHR₅, trans-CH═CHCO₂R₅,or trans-CH═CHCONHR₅ wherein R₅ is C₁₋₁₁ alkyl, phenyl C₁₋₁₁ alkyl, orC₁₋₆ alkoxycarbonylmethyleneoxy; R₂ and R₃ are each independentlyselected from the group consisting of mono-, di, and tri-substitutedphenyl wherein the substituents are independently selected from: (i)substituted C₁₋₆ alkyl; (ii) substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy,or substituted C₃₋₆ alkenyloxy; (iii) substituted C₁₋₆ alkyl-amino,di(substituted C₁₋₆ alkyl)amino; (iv) C₃₋₆ alkenyl-amino, di(C₃₋₆alkenyl)amino, substituted C₃₋₆ alkenyl-amino, or di(substituted C₃₋₆alkenyl)amino; and (v) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy-C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆ alkenyl)piperazino;wherein the substituents for (i), (ii), (iii), (iv), and (v) areselected from the group consisting of: (a) hydroxy, C₁₋₆ alkoxy, or C₁₋₆alkylamino; (b) C₃₋₆ alkenyloxy, or C₃₋₆ alkenylamino; and (c)pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl,piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino,4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆ alkyl)piperazino, or4-N—(C₁₋₆ alkylamino-C₃₋₆ alkenyl)piperazino; or R₂ and R₃ are takentogether to form an aryl group or substituted aryl, wherein thesubstituents are defined as above in (i)-(v); and R₄ is selected fromthe group consisting of: (i) hydrogen; (ii) substituted C₁₋₁₁ alkyl orC₂₋₁₁ alkenyl wherein the substituents are independently selected fromthe group consisting of hydrogen, hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio,C₁₋₆ alkylamino, phenyl-C₁₋₆ alkylamino, and C₁₋₆ alkoxycarbonyl; and(iii) substituted aryl C₀₋₁₁ alkyl wherein the aryl group is selectedfrom phenyl, imidazolyl, furyl, and thienyl in which the substituentsare selected from the group consisting of: (a) hydroxy, C₁₋₆ alkoxy, orC₁₋₆ alkylamino; (b) C₃₋₆ alkenyloxy, or C₃₋₆ alkenylamino; and (c)pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl,piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino,4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆ alkyl)piperazino, or4-N—(C₁₋₆ alkylamino-C₃₋₆ alkenyl)piperazino; or (B) R₁ is selected fromthe group consisting of: mono-, di-, and tri-substituted aryl-C₀₋₆ alkylwherein aryl is selected from the group consisting of phenyl andthienyl, and the substituents are selected from the group consisting of:(i) trans-2-substituted benzimidazolylethenyl, trans-2-substitutedbenzoxazolylethenyl, or trans-2-substituted benzthiazolylethenyl,wherein the substituents are selected from the group consisting ofhydrogen, hydroxy, halo, trihalomethyl, C₁₋₄ alkyl, C₁₋₄ alkyloxy, C₁₋₄alkyloxycarbonyl, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₃₋₆alkenylamino, di(C₃₋₆ alkenyl)amino, C₁₋₄ alkyloxy-C₁₋₄ alkylamino,substituted C₁₋₄ alkyl, substituted C₁₋₄ alkyloxy, substituted C₁₋₄alkyloxycarbonyl, substituted C₁₋₄ alkylamino, di(substituted C₁₋₄alkyl)amino, substituted C₃₋₆ alkenylamino, and di(substituted C₃₋₆alkenyl)amino, wherein the substituents are selected from the groupconsisting of: (a) hydroxy, C₁₋₆ alkoxy, or C₁₋₆ alkylamino; (b) C₃₋₆alkenyloxy, or C₃₋₆ alkenylamino; and (c) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N—C₁₋₆alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆alkylamino-C₁₋₆ alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆alkenyl)piperazino; (ii) trans-2-cyano ethenyl, trans-2-alkylsulfonylethenyl, trans-2-alkenylsulfonyl ethenyl, trans-2-substitutedalkylsulfonyl ethenyl, and trans-2-substituted alkenylsulfonyl ethenyl,wherein the substituents are selected from the group consisting of: (a)hydroxy, C₁₋₆ alkoxy, or C₁₋₆ alkylamino; (b) C₃₋₆ alkenyloxy, or C₃₋₆alkenylamino; and (c) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆ alkenyl)piperazino; (iii)C₁₋₆ CO₂R₅, trans-CH═CHCO₂R₅, C₁₋₆CONHR₅, or trans-CH═CHCONHR₅, whereinR₅ is C₁₋₆ alkoxy-C₂₋₆ alkyl, amino-C₂₋₄ alkyl, C₁₋₆ alkylamino-C₂₋₆alkyl, di(C₁₋₆ alkyl)amino-C₂₋₆ alkyl, C₁₋₆ alkylthio-C₂₋₆ alkyl,substituted C₁₋₆ alkoxy-C₂₋₆ alkyl, substituted C₁₋₆ alkylamino-C₂₋₆alkyl, di(substituted C₁₋₆ alkyl)amino-C₂₋₆ alkyl, or substituted C₁₋₆alkylthio-C₂₋₆ alkyl, wherein the substituents are selected from thegroup consisting of pyrrolidino, piperidino morpholino, piperazino,4-N—C₁₋₁₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆alkoxy-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy-C₃₋₆ alkenyl)piperazino,4-N—(C₁₋₆ alkylamino-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino, imidazolyl, oxazolyl, and thiazolyl; (iv)C₁₋₆CONHR₅, or trans-CH═CHCONR₆R₇, wherein R₆ and R₇ are independentlyselected from the group consisting of C₁₋₆ alkyl, phenyl-C₁₋₆ alkyl,C₁₋₆ alkoxycarbonylmethyleneoxy, hydroxy-C₂₋₆ alkyl, C₁₋₆ alkyloxy-C₂₋₆alkyl, amino-C₂₋₆ alkyl, C₁₋₆ alkylamino-C₂₋₆ alkyl, di(C₁₋₆alkyl)amino-C₂₋₆ alkyl, C₁₋₆ alkylthio-C₂₋₆ alkyl, substituted C₁₋₆alkoxy-C₂₋₆ alkyl, substituted C₁₋₆ alkylamino-C₂₋₆ alkyl,di(substituted C₁₋₆ alkyl)amino-C₂₋₆ alkyl, substituted C₁₋₆alkylthio-C₂₋₆ alkyl, wherein the substituents are selected from thegroup consisting of pyrrolidino, piperidino, morpholino, piperazino,4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxyC₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy-C₃₋₆ alkenyl)piperazino,4-N—(C₁₋₆ alkylamino-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₃₋₆alkenyl)piperazino, imidazolyl, oxazolyl, and thiazolyl; (v)R₇—C(O)—C₁₋₆ alkyl or R₇—C(O)—C₂₋₆ alkenyl, in which R₇ is defined asabove in [B(iv)]; (vi) HO—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇—O—C₁₋₆ alkyl-C₂₋₆alkenyl, R₇NH—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C(O)—O—C₁₋₆ alkyl-C₂₋₆alkenyl, R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, or R₇—C(O)—O—C₁₋₆alkyl-C₂₋₆ alkenyl, wherein R₆ and R₇ is defined as above in [B(iv)];and (vii) R₇—O—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl, R₇NH—C₀₋₃ alkyl-C₃₋₆cycloalk-1-yl, R₆R₇N—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl, R₇NH—C(O)—O—C₀₋₃C₃₋₆ cycloalk-1-yl, R₆R₇N—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl,R₇O—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl, R₇—C(O)—O—C₀₋₃ alkyl-C₃₋₆cycloalk-1-yl, R₇O—C(O)—Co-3 alkyl-C₃₋₆ cycloalk-1-yl, wherein R₇ and R₆are defined as above in [B(iv)]; R₂ and R₃ are each independentlyselected from the group consisting of: (viii) hydrogen, halo,trihalomethyl, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₂₋₆ alkenyl,substituted C₂₋₆ alkenyl, C₁₋₆ alkyloxy, substituted C₁₋₆ alkyloxy, C₃₋₆alkenyloxy, substituted C₃₋₆ alkenyloxy, C₁₋₆ alkylamino, substitutedC₁₋₆ alkylamino, C₃₋₆ alkenylamino, or substituted C₃₋₆ alkenylamino;and (ix) mono-, di-, or tri-substituted phenyl wherein the substituentsare independently selected from the group consisting of: (a) halo,trifluoromethyl, or substituted C₁₋₆ alkyl; (b) C₁₋₆ alkyloxy,substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy, substituted C₃₋₆ alkenyloxy;(c) C₁₋₆ alkyl-amino, di(C₁₋₆ alkyl)amino, substituted C₁₋₆ alkyl-amino,di(substituted C₁₋₆ alkyl)amino, C₃₋₆ alkenyl-amino, di(C₃₋₆alkenyl)amino, substituted C₃₋₆ alkenyl-amino, or di(substituted C₃₋₆alkenyl)amino; and (d) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino;wherein the substituents for (a), (b), (c), and (d) are selected fromthe group consisting of: (1) hydrogen, hydroxy, halo, ortrifluoromethyl; (2) C₁₋₆ alkylalkoxy, C₁₋₆ alkylamino, or C₁₋₆alkylthio; (3) C₃₋₆ alkenyloxy, C₃₋₆ alkenylamino, or C₃₋₆ alkenylthio;and (4) pyrrolidino, piperidino, morpholino, imidazolyl, substitutedimidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino; withthe proviso that a) at least one of R₂ and R₃ is selected from [B (ix)]and wherein the substituents are selected from [B (ix) (b)-(d)] above;or b) R₂ and R₃ are taken together to form an optionally substitutedaryl group, wherein the substituents are defined as above in [B (ix)(a)-(d)]; and R₄ is selected from the group consisting of: (i) hydrogen;(ii) substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the substituentsare independently selected from the group consisting of: (a) hydrogen,hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio, C₁₋₆ alkylamino, phenyl-C₁₋₆alkylamino, or C₁₋₆ alkoxycarbonyl; (b) substituted C₁₋₆ alkyloxy, C₃₋₆alkenyloxy, or substituted C₃₋₆ alkenyloxy; (c) di(C₁₋₆ alkyl)amino,substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆ alkyl)amino, C₃₋₆alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆ alkenyl-amino, ordi(substituted C₃₋₆ alkenyl)amino; and (d) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N—C₁₋₆alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆alkylamino C₁₋₆ alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino; and (iii) aryl C₀₋₁₁ alkyl wherein the aryl group isselected from phenyl, imidazolyl, furyl, or thienyl, and a secondcompound effective to treat the lipid storage disease.
 19. The method ofclaim 17 or 18 wherein the second compound is a glucosylceramidesynthase inhibitor.
 20. The method of claim 19, wherein theglucosylceramide synthase inhibitor is miglustat.
 21. The method ofclaim 17 or 18 wherein the second compound is an enzyme administered asenzyme replacement therapy.
 22. The method of claim 17 or 18 wherein thesecond compound is a pharmacological chaperone which binds to an enzymeand promotes trafficking of the enzyme from the endoplasmic reticulum tothe lysosome.
 23. A composition comprising a glucosylceramide synthaseinhibitor and compound of Formula 1

in the form of a free compound or its pharmaceutically acceptablepro-drug, metabolite, analogue, derivative, solvate or salt wherein thesubstituents R₁, R₂, R₃, and R₄ are defined as described in A and Bbelow: (a) when R₁ is selected from the group consisting of: (i)substituted C₁₋₁₁ alkyl or substituted C₂₋₁₁ alkenyl, wherein thesubstituents are selected from the group consisting of hydroxy, C₁₋₆alkyloxy; or (ii) mono-, di-, and tri-substituted aryl-C₀₋₁₁ alkylwherein aryl is selected from the group consisting of phenyl, furyl,thienyl wherein the substituents are selected from the group consistingof: (a) phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl,wherein the said phenyl group is mono- or disubstituted with a memberselected from the group consisting of hydroxy, halo, C₁₋₄ alkyl and C₁₋₄alkyloxy, (b) substituted C₁₋₆ alkyl, substituted C₂₋₆ alkyloxy,substituted C₂₋₆ alkylthio, substituted C₂₋₆ alkoxycarbonyl, wherein thesubstituents are selected from the group consisting of C₁₋₆ alkoxy, andC₁₋₆ alkylthio; and (c) C₁₋₁₁ CO₂R₅, C₁₋₁₁CONHR₅, trans-CH═CHCO₂R₅, ortrans-CH═CHCONHR₅ wherein R₅ is C₁₋₁₁ alkyl, or phenyl C₁₋₆ alkyl, C₁₋₆alkoxycarbonylmethyleneoxy; then R₂ and R₃ are each independentlyselected from the group consisting of mono-, di, and tri-substitutedphenyl wherein the substituents are independently selected from: (i)substituted C₁₋₆ alkyl, (ii) substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy,substituted C₃₋₆ alkenyloxy, (iii) substituted C₁₋₆ alkyl-amino,di(substituted C₁₋₆ alkyl)amino, (iv) C₃₋₆ alkenyl-amino, di(C₃₋₆alkenyl)amino, substituted C₃₋₆ alkenyl-amino, di(substituted C₃₋₆alkenyl)amino, (v) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino, whereinthe substituents are selected from the group consisting of: (a) hydroxy,C₁₋₆ alkylalkoxy, C₁₋₆ alkylamino (b) C₃₋₆ alkenyloxy, C3-6alkenylamino, or (c) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino, or R₂and R₃ taken together forming an aryl group or substituted aryl, whereinthe substituents are defined as above in (i)-(v); and R₄ is selectedfrom the group consisting of: (i) hydrogen; (ii) substituted C₁₋₁₁ alkylor C₂₋₁₁ alkenyl wherein the substituents are independently selectedfrom the group consisting of hydrogen, hydroxy, C₁₋₆ alkyloxy,C₁₋₆alkylthio, C₁₋₆ alkylamino, phenyl-C₁₋₆ alkylamino, C₁₋₆alkoxycarbonyl; or (iii) substituted aryl C₀₋₁₁ alkyl wherein the arylgroup is selected from phenyl, imidazolyl, furyl, thienyl in which thesubstituents are selected from A(a-c); or (b) when R₁ is selected fromthe group consisting of: Mono-, di-, and tri-substituted aryl-C₀₋₆ alkylwherein aryl is selected from the group consisting of phenyl, thienyl,and the substituents are selected from the group consisting of: (a)trans-2-substituted benzimidazolylethenyl, trans-2-substitutedbenzoxazolylethenyl, trans-2-substituted benzthiazolylethenyl, in whichthe substituents are selected from the group consisting of hydrogen,hydroxy, halo, trihalomethyl, C₁₋₄ alkyl and C₁₋₄ alkyloxy, C₁₋₄alkyloxycarbonyl, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₃₋₆alkenylamino, di(C₃₋₆ alkenyl)amino, C₁₋₄ alkyloxy-C₁₋₄ alkylamino,substituted C₁₋₄ alkyl and C₁₋₄ alkyloxy, substituted C₁₋₄alkyloxycarbonyl, substituted C₁₋₄ alkylamino, di(substituted C₁₋₄alkyl)amino, substituted C₃₋₆ alkenylamino, di(substituted C₃₋₆alkenyl)amino, wherein the substituents are as defined above, (b)trans-2-cyano ethenyl, trans-2-alkylsulfonyl ethenyl,trans-2-alkenylsulfonyl ethenyl, trans-2-substituted alkylsulfonylethenyl, trans-2-substituted alkenylsulfonyl ethenyl, in which thesubstituents are defined above, (c) C₁₋₆ CO₂R₅, trans-CH═CHCO₂R₃,C₁₋₆CONHR₅, or trans-CH═CHCONHR₅, wherein R₅ is C₁₋₆ alkoxy C₂₋₆ alkyl,amino C₂₋₆ alkyl, C₁₋₆ alkylamino C₂₋₆ alkyl, di(C₁₋₆ alkyl)amino C₂₋₆alkyl, C₁₋₆ alkylthio C₂₋₆ alkyl, substituted C₁₋₆ alkoxy C₂₋₆ alkyl,substituted C₁₋₆ alkylamino C₂₋₆ alkyl, di(substituted C₁₋₆ alkyl)aminoC₂₋₆ alkyl, substituted C₁₋₆ alkylthio C₂₋₆ alkyl, in which thesubstituents are selected from the group consisting of pyrrolidino,piperidino morpholino, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₄ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino,imidazolyl, oxazolyl, thiazolyl, (d) C₁₋₆CONR₆R₇, or trans-CH—CHCONR₆R₇,wherein T % and R₇ are independently selected from the group consistingof C₁₋₆ alkyl, phenyl C₁₋₆ alkyl, C₁₋₆ alkoxycarbonylmethyleneoxy,hydroxy C₂₋₆ alkyl, C₁₋₆ alkyloxy C₂₋₆ alkyl, amino C₂₋₆ alkyl, C₁₋₄alkylamino C₂₋₆ alkyl, di(C₁₋₆ alkyl)amino C₂₋₆ alkyl, C₁₋₆ alkylthioC₂₋₆ alkyl, substituted C₁₋₆ alkoxy C₂₋₆ alkyl, substituted C₁₋₆alkylamino C₂₋₆ alkyl, di(substituted C₁₋₆ alkyl)amino C₂₋₆ alkyl,substituted C₁₋₆ alkylthio C₂₋₆ alkyl, wherein the substituents areselected from the group consisting of pyrrolidino, piperidino,morpholino, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino,imidazolyl, oxazolyl, thiazolyl, (e) R₇ C(O) C₁₋₆ alkyl, R₇ C(O)C₂₋₆alkenyl, in which R₇ is defined as above [2(d)], (f) HO—C₁₋₆ alkyl-C₂₋₄alkenyl, R₇—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₆R₇N—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆alkenyl, R₇—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, wherein R₆ and R₇ is definedas above [2(d)], (g) R₇—O—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl, R₇NH—C₀₋₃alkyl-C₃₋₆ cycloalkan-1-yl, R₆R₇N—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl,R₇NH—C(O)—O—C₀₋₃ C₃₋₆ cycloalkan-1-yl, R₆R₇N—C(O)—O—CO₀₋₃ alkyl-C₃₋₆cycloalkan-1-yl, R₇O—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl,R₇—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl, R₇O—C(O)—Co-3 alkyl-C₃₋₆cycloalkan-1-yl, wherein R₇ and is defined as above [B(d)]; then R₂ andR₃ are each independently selected from the group consisting of: (1)hydrogen, halo, trihalomethyl, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₂₋₆alkenyl, substituted C₁₋₆ alkenyl, C₁₋₆ alkyloxy, substituted C₁₋₆alkyloxy, C₃₋₆ alkenyloxy, substituted C₃₋₆ alkenyloxy, C₁₋₆ alkylamino,substituted C₁₋₆ alkylamino, C₃₋₆ alkenylamino, substituted C₃₋₆alkenylamino, (2) mono-, di-, and tri-substituted phenyl wherein thesubstituents are independently selected from: (i) halo, trifluoromethyl,substituted C₁₋₆ alkyl, (ii) C₁₋₆ alkyloxy, substituted C₁₋₆ alkyloxy,C₃₋₆ alkenyloxy, substituted C₃₋₆ alkenyloxy, (iii) C₁₋₆ alkyl-amino,di(C₁₋₆ alkyl)amino, substituted C₁₋₄ alkyl-amino, di(substituted C₁₋₆alkyl)amino, C₃₋₆ alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆alkenyl-amino, di(substituted C₃₋₆ alkenyl)amino, or (iv) pyrrolidino,piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino,4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxyC₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino,4-N—(C₁₋₆ alkylamino C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino, wherein the substituents are selected from the groupconsisting of: (a) hydrogen, hydroxy, halo, trifluoromethyl, (b) C₁₋₆alkylalkoxy, C₁₋₆ alkylamino, C₁₋₆ alkylthio, (c) C₃₋₆ alkenyloxy, C₃₋₆alkenylamino, C₃₋₆ alkenylthio, or (d) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N—C₁₋₆alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆alkylamino C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino; with the proviso that at least one of R₂ and R₃group be selected from [B (2)] and the phenyl and the substituents beselected from (ii)-(v) above; or R₂ and R₃ taken together forming anaryl group such as phenyl, pyridyl, in which the aryl may be optionallysubstituted, wherein the substituents are defined as above in (i)-(iv);and R₄ is selected from the group consisting of: (a) hydrogen; (b)substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the substituents areindependently selected from the group consisting of: (i) hydrogen,hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio, C₁₋₆ alkylamino, phenyl-C₁₋₆alkylamino, C₁₋₆ alkoxycarbonyl; (ii) substituted C₁₋₆ alkyloxy, C₃₋₆alkenyloxy, substituted C₃₋₆ alkenyloxy, (iii) di(C₁₋₆ alkyl)amino,substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆ alkyl)amino, C₃₋₆alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆ alkenyl-amino,di(substituted C₃₋₆ alkenyl)amino; and (iv) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N—C₁₋₆alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆alkylamino C₁₋₆ alkyl)piperazino, and 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino; and (c) aryl C₀₋₁₁ alkyl wherein the aryl group isselected from phenyl, imidazolyl, furyl, thienyl.
 24. A compositioncomprising a glucosylceramide synthase inhibitor and compound of Formula1a:

in the form of a free compound or its pharmaceutically acceptablepro-drug, metabolite, analogue, derivative, solvate or salt wherein thesubstituents R₁, R₂, R₃, and R₄ are defined as described in A and Bbelow: (A) R₁ is selected from the group consisting of: (i) substitutedC₁₋₁₁ alkyl or substituted C₂₋₁₁ alkenyl, wherein the substituents areselected from the group consisting of hydroxy and C₁₋₆ alkyloxy; and(ii) mono-, di-, or tri-substituted aryl-C₀₋₁₁ alkyl wherein aryl isselected from the group consisting of phenyl, furyl, and thienyl whereinthe substituents are selected from the group consisting of: (a) phenyl,trans-2-phenylethenyl, 2-phenylethynyl, or 2-phenylethyl, wherein thephenyl group is mono- or disubstituted wherein the substituents areselected from the group consisting of hydroxy, halo, C₁₋₄ alkyl and C₁₋₄alkyloxy; (b) substituted C₁₋₆ alkyl, substituted C₂₋₆ alkyloxy,substituted C₂₋₆ alkylthio, or substituted C₂₋₆ alkoxycarbonyl, whereinthe substituents are selected from the group consisting of C₁₋₆ alkoxy,and C₁₋₆ alkylthio; and (c) C₁₋₁₁ CO₂R₅, C₁₋₁₁CONHR₅, trans-CH═CHCO₂R₅,or trans-CH═CHCONHR₅ wherein R₅ is C₁₋₁₁ alkyl, phenyl C₁₋₁₁ alkyl, orC₁₋₆ alkoxycarbonylmethyleneoxy; R₂ and R₃ are each independentlyselected from the group consisting of mono-, di, and tri-substitutedphenyl wherein the substituents are independently selected from: (i)substituted C₁₋₆ alkyl; (ii) substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy,or substituted C₃₋₆ alkenyloxy; (iii) substituted C₁₋₆ alkyl-amino,di(substituted C₁₋₆ alkyl)amino; (iv) C₃₋₆ alkenyl-amino, di(C₃₋₆alkenyl)amino, substituted C₃₋₆ alkenyl-amino, or di(substituted C₃₋₆alkenyl)amino; and (v) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy-C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆ alkenyl)piperazino;wherein the substituents for (i), (ii), (iii), (iv), and (v) areselected from the group consisting of: (a) hydroxy, C₁₋₆ alkoxy, or C₁₋₆alkylamino; (b) C₃₋₆ alkenyloxy, or C₃₋₆ alkenylamino; and (c)pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl,piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino,4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆ alkyl)piperazino, or4-N—(C₁₋₆ alkylamino-C₃₋₆ alkenyl)piperazino; or R₂ and R₃ are takentogether to form an aryl group or substituted aryl, wherein thesubstituents are defined as above in (i)-(v), and R₄ is selected fromthe group consisting of: (i) hydrogen; (ii) substituted C₁₋₁₁ alkyl orC₂₋₁₁ alkenyl wherein the substituents are independently selected fromthe group consisting of hydrogen, hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio,C₁₋₆ alkylamino, phenyl-C₁₋₆ alkylamino, and C₁₋₆ alkoxycarbonyl; and(iii) substituted aryl C₀₋₁₁ alkyl wherein the aryl group is selectedfrom phenyl, imidazolyl, furyl and thienyl wherein the substituents areselected from the group consisting of: (a) hydroxy, C₁₋₆ alkoxy, or C₁₋₆alkylamino; (b) C₃₋₆ alkenyloxy, or C₃₋₆ alkenylamino; and (c)pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl,piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino,4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆ alkyl)piperazino, or4-N—(C₁₋₆ alkylamino-C₃₋₆ alkenyl)piperazino; or (B) R₁ is selected fromthe group consisting of: mono-, di-, and tri-substituted aryl-C₀₋₆ alkylwherein aryl is selected from the group consisting of phenyl andthienyl, and the substituents are selected from the group consisting of:(i) trans-2-substituted benzimidazolylethenyl, trans-2-substitutedbenzoxazolylethenyl, or trans-2-substituted benzthiazolylethenyl whereinthe substituents are selected from the group consisting of hydrogen,hydroxy, halo, trihalomethyl, C₁₋₄ alkyl, C₁₋₄ alkyloxy, C₁₋₄alkyloxycarbonyl, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₃₋₆alkenylamino, di(C₃₋₆ alkenyl)amino, C₁₋₄ alkyloxy-C₁₋₄ alkylamino,substituted C₁₋₄ alkyl, substituted C₁₋₄ alkyloxy, substituted C₁₋₄alkyloxycarbonyl, substituted C₁₋₄ alkylamino, di(substituted C₁₋₄alkyl)amino, substituted C₃₋₆ alkenylamino, and di(substituted C₃₋₆alkenyl)amino, wherein the substituents are selected from the groupconsisting of: (a) hydroxy, C₁₋₆ alkoxy, or C₁₋₆ alkylamino; (b) C₃₋₆alkenyloxy, or C₃₋₆ alkenylamino; and (c) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N—C₁₋₆alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆alkylamino-C₁₋₆ alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆alkenyl)piperazino; (ii) trans-2-cyano ethenyl, trans-2-alkylsulfonylethenyl, trans-2-alkenylsulfonyl ethenyl, trans-2-substitutedalkylsulfonyl ethenyl, and trans-2-substituted alkenylsulfonyl ethenyl,wherein the substituents are selected from the group consisting of: (a)hydroxy, C₁₋₆ alkoxy, or C₁₋₆ alkylamino; (b) C₃₋₆ alkenyloxy, or C₃₋₆alkenylamino; and (c) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆ alkenyl)piperazino; (iii)C₁₋₆ CO₂R₅, trans-CH═CHCO₂R₅, C₁₋₆CONHR₅, or trans-CH═CHCONHR₅, whereinR₅ is C₁₋₆ alkoxy-C₂₋₆ alkyl, amino-C₂₋₆ alkyl, C₁₋₄ alkylamino-C₂₋₆alkyl, di(C₁₋₆ alkyl)amino-C₂₋₆ alkyl, C₁₋₆ alkylthio-C₂₋₆ alkyl,substituted C₁₋₆ alkoxy-C₂₋₆ alkyl, substituted C₁₋₆ alkylamino-C₂₋₆alkyl, di(substituted C₁₋₆ alkyl)amino-C₂₋₆ alkyl, or substituted C₁₋₆alkylthio-C₂₋₆ alkyl, in which the substituents are selected from thegroup consisting of pyrrolidino, piperidino morpholino, piperazino,4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆alkoxy-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy-C₃₋₆ alkenyl)piperazino,4-N—(C₁₋₆ alkylamino-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino, imidazolyl, oxazolyl, and thiazolyl; (iv)C₁₋₆CONHR₅, or trans-CH═CHCONR₆R₇, wherein R₆ and R₇ are independentlyselected from the group consisting of C₁₋₆ alkyl, phenyl-C₁₋₆ alkyl,C₁₋₆ alkoxycarbonylmethyleneoxy, hydroxy-C₂₋₆ alkyl, C₁₋₆ alkyloxy-C₂₋₆alkyl, amino-C₂₋₆ alkyl, C₁₋₆ alkylamino-C₂₋₆ alkyl, di(C₁₋₆alkyl)amino-C₂₋₆ alkyl, C₁₋₆ alkylthio-C₂₋₆ alkyl, substituted C₁₋₆alkoxy-C₂₋₆ alkyl, substituted C₁₋₆ alkylamino-C₂₋₆ alkyl,di(substituted C₁₋₆ alkyl)amino-C₂₋₆ alkyl, substituted C₁₋₆alkylthio-C₂₋₆ alkyl, wherein the substituents are selected from thegroup consisting of pyrrolidino, piperidino, morpholino, piperazino,4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxyC₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy-C₃₋₆ alkenyl)piperazino,4-N—(C₁₋₆ alkylamino-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₃₋₆alkenyl)piperazino, imidazolyl, oxazolyl, and thiazolyl; (v)R₇—C(O)—C₁₋₆ alkyl or R₇—C(O)—C₂₋₆ alkenyl, in which R₇ is defined asabove in [B(iv)] (vi) HO—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇—O—C₁₋₆ alkyl-C₂₋₆alkenyl, R₇NH—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C(O)—O—C₁₋₆ alkyl-C₂₋₆alkenyl, R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, or R₇—C(O)—O—C₁₋₆alkyl-C₂₋₆ alkenyl, wherein R₆ and R₇ is defined as above in [B(iv)];and (vii) R₇—O—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl, R₇NH—C₀₋₃ alkyl-C₃₋₆cycloalk-1-yl, R₆R₇N—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl, R₇NH—C(O)—O—C₀₋₃C₃₋₆ cycloalk-1-yl, R₆R₇N—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl,R₇O—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl, R₇—C(O)—O—C₀₋₃ alkyl-C₃₋₆cycloalk-1-yl, R₇O—C(O)—Co-3 alkyl-C₃₋₆ cycloalk-1-yl, wherein R₇ and R₆are defined as above in [B(iv)]; R₂ and R₃ are each independentlyselected from the group consisting of: (viii) hydrogen, halo,trihalomethyl, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₂₋₆ alkenyl,substituted C₂₋₆ alkenyl, C₁₋₆ alkyloxy, substituted C₁₋₆ alkyloxy, C₃₋₆alkenyloxy, substituted C₃₋₆ alkenyloxy, C₁₋₆ alkylamino, substitutedC₁₋₆ alkylamino, C₃₋₆ alkenylamino, or substituted C₃₋₆ alkenylamino;and (ix) mono-, di-, or tri-substituted phenyl wherein the substituentsare independently selected from the group consisting of: (a) halo,trifluoromethyl, or substituted C₁₋₆ alkyl; (b) C₁₋₆ alkyloxy,substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy, substituted C₃₋₆ alkenyloxy;(c) C₁₋₆ alkyl-amino, di(C₁₋₆ alkyl)amino, substituted C₁₋₆ alkyl-amino,di(substituted C₁₋₆ alkyl)amino, C₃₋₆ alkenyl-amino, di(C₃₋₆alkenyl)amino, substituted C₃₋₆ alkenyl-amino, or di(substituted C₃₋₆alkenyl)amino; and (d) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino;wherein the substituents for (a), (b), (c), and (d) are selected fromthe group consisting of: (1) hydrogen, hydroxy, halo, ortrifluoromethyl; (2) C₁₋₆ alkylalkoxy, C₁₋₆ alkylamino, or C₁₋₆alkylthio; (3) C₃₋₆ alkenyloxy, C₃₋₆ alkenylamino, or C₃₋₆ alkenylthio;and (4) pyrrolidino, piperidino, morpholino, imidazolyl, substitutedimidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino; withthe proviso that a) at least one of R₂ and R₃ is selected from [B (ix)]and wherein the substituents are selected from [B (ix) (b)-(d)] above;or b) R₂ and R₃ are taken together to form an optionally substitutedaryl group, wherein the substituents are defined as above in [B (ix)(a)-(d)]; and R₄ is selected from the group consisting oft (i) hydrogen;(ii) substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the substituentsare independently selected from the group consisting of: (a) hydrogen,hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio, C₁₋₆ alkylamino, phenyl-C₁₋₆alkylamino, or C₁₋₆ alkoxycarbonyl; (b) substituted C₁₋₆ alkyloxy, C₃₋₆alkenyloxy, or substituted C₃₋₆ alkenyloxy; (c) di(C₁₋₆ alkyl)amino,substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆ alkyl)amino, C₃₋₆alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆ alkenyl-amino, ordi(substituted C₃₋₆ alkenyl)amino; and (d) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N—C₁₋₆alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆alkylamino C₁₋₆ alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino; and (iii) aryl C₀₋₁₁ alkyl wherein the aryl group isselected from phenyl, imidazolyl, furyl, or thienyl.
 25. The compositionof claim 23 or 24 wherein the glucosylceramide synthase inhibitor ismiglustat.
 26. The composition of claim 23 or 24 wherein the compound ofFormula 1 or 1a has the following formula (Formula 2):

in the form of a free compound or as its pharmaceutically-acceptablepro-drug, metabolite, analogue, derivative, solvate or salt.
 27. Amethod of treating a subject having a condition associated withverotoxin, cholera toxin or uropathic E. coli comprising administeringto the subject an effective amount of a compound of Formula 1:

in the form of a free compound or its pharmaceutically acceptablepro-drug, metabolite, analogue, derivative, solvate or salt wherein thesubstituents R₁, R₂, R₃, and R₄ are defined as described in A and Bbelow: (a) when R₁ is selected from the group consisting of: (i)substituted C₁₋₁₁ alkyl or substituted C₂₋₁₁ alkenyl, wherein thesubstituents are selected from the group consisting of hydroxy, C₁₋₆alkyloxy; or (ii) mono-, di-, and tri-substituted aryl-C₀₋₁₁ alkylwherein aryl is selected from the group consisting of phenyl, furyl,thienyl wherein the substituents are selected from the group consistingof: (a) phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl,wherein the said phenyl group is mono- or disubstituted with a memberselected from the group consisting of hydroxy, halo, C₁₋₄ alkyl and C₁₋₄alkyloxy, (b) substituted C₁₋₆ alkyl, substituted C₂₋₆ alkyloxy,substituted C₂₋₆ alkylthio, substituted C₂₋₆ alkoxycarbonyl, wherein thesubstituents are selected from the group consisting of C₁₋₆ alkoxy, andC₁₋₆ alkylthio; and (c) C₁₋₁₁ CO₂R₅, C₁₋₁₁ CONHR₅, trans-CH═CHCO₂R₅, ortrans-CH═CHCONHR₅ wherein R₅ is C₁₋₁₁ alkyl, or phenyl C₁₋₁₁ alkyl, C₁₋₆alkoxycarbonylmethyleneoxy; then R₂ and R₃ are each independentlyselected from the group consisting of mono-, di, and tri-substitutedphenyl wherein the substituents are independently selected from: (i)substituted C₁₋₆ alkyl, (ii) substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy,substituted C₃₋₆ alkenyloxy, (iii) substituted C₁₋₆ alkyl-amino,di(substituted C₁₋₆ alkyl)amino, (iv) C₃₋₆ alkenyl-amino, di(C₃₋₆alkenyl)amino, substituted C₃₋₆ alkenyl-amino, di(substituted C₃₋₆alkenyl)amino, (v) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino, whereinthe substituents are selected from the group consisting of: (a) hydroxy,C₁₋₆ alkylalkoxy, C₁₋₆ alkylamino (b) C₃₋₆ alkenyloxy, C3-6alkenylamino, or (c) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino, or R₂and R₃ taken together forming an aryl group or substituted aryl, whereinthe substituents are defined as above in (i)-(v); and R₄ is selectedfrom the group consisting of: (i) hydrogen; (ii) substituted C₁₋₁₁ alkylor C₂₋₁₁ alkenyl wherein the substituents are independently selectedfrom the group consisting of hydrogen, hydroxy, C₁₋₆ alkyloxy,C₁₋₆alkylthio, C₁₋₆ alkylamino, phenyl-C₁₋₆ alkylamino, C₁₋₆alkoxycarbonyl; or (iii) substituted aryl C₀₋₁₁ alkyl wherein the arylgroup is selected from phenyl, imidazolyl, furyl, thienyl in which thesubstituents are selected from A(a-c); or (b) when R₁ is selected fromthe group consisting of: Mono-, di-, and tri-substituted aryl-C₀₋₆ alkylwherein aryl is selected from the group consisting of phenyl, thienyl,and the substituents are selected from the group consisting of: (a)trans-2-substituted benzimidazolylethenyl, trans-2-substitutedbenzoxazolylethenyl, trans-2-substituted benzthiazolylethenyl, in whichthe substituents are selected from the group consisting of hydrogen,hydroxy, halo, trihalomethyl, C₁₋₄ alkyl and C₁₋₄ alkyloxy, C₁₋₄alkyloxycarbonyl, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₃₋₆alkenylamino, di(C₃₋₆ alkenyl)amino, C₁₋₄ alkyloxy-C₁₋₄ alkylamino,substituted C₁₋₄ alkyl and C₁₋₄ alkyloxy, substituted C₁₋₄alkyloxycarbonyl, substituted C₁₋₄ alkylamino, di(substituted C₁₋₄alkyl)amino, substituted C₃₋₆ alkenylamino, di(substituted C₃₋₆alkenyl)amino, wherein the substituents are as defined above, (b)trans-2-cyano ethenyl, trans-2-alkylsulfonyl ethenyl,trans-2-alkenylsulfonyl ethenyl, trans-2-substituted alkylsulfonylethenyl, trans-2-substituted alkenylsulfonyl ethenyl, in which thesubstituents are defined above, (c) C₁₋₆ CO₂R₅, trans-CH═CHCO₂R₅,C₁₋₆CONHR₅, or trans-CH═CHCONHR₅, wherein R₅ is C₁₋₆ alkoxy C₂₋₆ alkyl,amino C₂₋₆ alkyl, C₁₋₆ alkylamino C₂₋₆ alkyl, di(C₁₋₆ alkyl)amino C₂₋₆alkyl, C₁₋₆ alkylthio C₂₋₆ alkyl, substituted C₁₋₆ alkoxy C₂₋₆ alkyl,substituted C₁₋₆ alkylamino C₂₋₆ alkyl, di(substituted C₁₋₆ alkyl)aminoC₂₋₆ alkyl, substituted C₁₋₆ alkylthio C₂₋₆ alkyl, in which thesubstituents are selected from the group consisting of pyrrolidino,piperidino morpholino, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino,imidazolyl, oxazolyl, thiazolyl, (d) C₁₋₆CONR₆R₇, or trans-CH═CHCONR₆R₇,wherein R₆ and R₇ are independently selected from the group consistingof C₁₋₆ alkyl, phenyl C₁₋₆ alkyl, C₁₋₆ alkoxycarbonylmethyleneoxy,hydroxy C₂₋₆ alkyl, C₁₋₆ alkyloxy C₂₋₆ alkyl, amino C₂₋₆ alkyl, C₁₋₆alkylamino C₂₋₆ alkyl, di(C₁₋₆ alkyl)amino C₂₋₆ alkyl, C₁₋₆ alkylthioC₂₋₆ alkyl, substituted C₁₋₆ alkoxy C₂₋₆ alkyl, substituted C₁₋₆alkylamino C₂₋₆ alkyl, di(substituted C₁₋₆ alkyl)amino C₂₋₆ alkyl,substituted C₁₋₆ alkylthio C₂₋₆ alkyl, wherein the substituents areselected from the group consisting of pyrrolidino, piperidino,morpholino, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino,imidazolyl, oxazolyl, thiazolyl, (e) R₇ C(O) C₁₋₆ alkyl, R₇ C(O)C₂₋₆alkenyl, in which R₇ is defined as above [2(d)], (f) HO—C₁₋₆ alkyl-C₂₋₆alkenyl, R₇—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₆R₇N—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆alkenyl, R₇—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, wherein R₆ and R₇ is definedas above [2(d)], (g) R₇—O—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl, R₇NH—C₀₋₃alkyl-C₃₋₆ cycloalkan-1-yl, R₆R₇N—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl,R₇NH—C(O)—O—C₀₋₃ C₃₋₆ cycloalkan-1-yl, R₆R₇N—C(O)—O—C₀₋₃ alkyl-C₃₋₆cycloalkan-1-yl, R₇O—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl,R₇—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalkan-1-yl, R₇O—C(O)—Co-3 alkyl-C₃₋₆cycloalkan-1-yl, wherein R₇ and is defined as above [B(d)]; then R₂ andR₃ are each independently selected from the group consisting of: (1)hydrogen halo, trihalomethyl, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₂₋₆alkenyl, substituted C₁₋₆ alkenyl, C₁₋₆ alkyloxy, substituted C₁₋₆alkyloxy, C₃₋₆ alkenyloxy, substituted C₃₋₆ alkenyloxy, C₁₋₆ alkylamino,substituted C₁₋₆ alkylamino, C₃₋₆ alkenylamino, substituted C₃₋₆alkenylamino, (2) mono-, di-, and tri-substituted phenyl wherein thesubstituents are independently selected from: (i) halo, trifluoromethyl,substituted C₁₋₆ alkyl, (ii) C₁₋₆ alkyloxy, substituted C₁₋₄ alkyloxy,C₃₋₆ alkenyloxy, substituted C₃₋₆ alkenyloxy, (iii) C₁₋₆ alkyl-amino,di(C₁₋₆ alkyl)amino, substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆alkyl)amino, C₃₋₆ alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆alkenyl-amino, di(substituted C₃₋₆ alkenyl)amino, or (iv) pyrrolidino,piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino,4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxyC₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino,4-N—(C₁₋₆ alkylamino C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino, wherein the substituents are selected from the groupconsisting of: (a) hydrogen, hydroxy, halo, trifluoromethyl, (b) C₁₋₆alkylalkoxy, C₁₋₆ alkylamino, C₁₋₆ alkylthio, (c) C₃₋₆ alkenyloxy, C₃₋₆alkenylamino, C₃₋₆ alkenylthio, or (d) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N—C₁₋₆alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆alkylamino C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino; with the proviso that at least one of R₂ and R₃group be selected from [B (2)] and the phenyl and the substituents beselected from (ii)-(v) above; or R₂ and R₃ taken together forming anaryl group such as phenyl, pyridyl, in which the aryl may be optionallysubstituted, wherein the substituents are defined as above in (i)-(iv);and R₄ is selected from the group consisting of: (a) hydrogen; (b)substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the substituents areindependently selected from the group consisting of: (i) hydrogen,hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio, C₁₋₄ alkylamino, phenyl-C₁₋₆alkylamino, C₁₋₆ alkoxycarbonyl; (ii) substituted C₁₋₆ alkyloxy, C₃₋₆alkenyloxy, substituted C₃₋₆ alkenyloxy, (iii) di(C₁₋₆ alkyl)amino,substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆ alkyl)amino, C₃₋₆alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆ alkenyl-amino,di(substituted C₃₋₆ alkenyl)amino; and (iv) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N—C₁₋₆alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆alkylamino C₁₋₆ alkyl)piperazino, and 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino; and (c) aryl C₀₋₁₁ alkyl wherein the aryl group isselected from phenyl, imidazolyl, furyl, thienyl.
 28. A method oftreating a subject having a condition associated with verotoxin, choleratoxin or uropathic E. coli comprising administering to the subject aneffective amount of a compound of Formula 1a:

in the form of a free compound or its pharmaceutically acceptablepro-drug, metabolite, analogue, derivative, solvate or salt wherein thesubstituents R₁, R₂, R₃, and R₄ are defined as described in A and Bbelow: (A) R₁ is selected from the group consisting of: (i) substitutedC₁₋₁₁ alkyl or substituted C₂₋₁₁ alkenyl, wherein the substituents areselected from the group consisting of hydroxy and C₁₋₆ alkyloxy; and(ii) mono-, di-, or tri-substituted aryl-C₀₋₁₁ alkyl wherein aryl isselected from the group consisting of phenyl, furyl, and thienyl whereinthe substituents are selected from the group consisting of: (a) phenyl,trans-2-phenylethenyl, 2-phenylethynyl, or 2-phenylethyl, wherein thephenyl group is mono- or disubstituted wherein the substituents areselected from the group consisting of hydroxy, halo, C₁₋₄ alkyl and C₁₋₄alkyloxy; (b) substituted C₁₋₆ alkyl, substituted C₂₋₆ alkyloxy,substituted C₂₋₆ alkylthio, or substituted C₂₋₆ alkoxycarbonyl, whereinthe substituents are selected from the group consisting of C₁₋₄ alkoxy,and C₁₋₆ alkylthio; and (c) C₁₋₁₁ CO₂R₅, C₁₋₁₁CONHR₅, trans-CH═CHCO₂R₅,or trans-CH═CHCONHR₅ wherein R₅ is C₁₋₁₁ alkyl, phenyl C₁₋₁₁ alkyl, orC₁₋₆ alkoxycarbonylmethyleneoxy; R₂ and R₃ are each independentlyselected from the group consisting of mono-, di, and tri-substitutedphenyl wherein the substituents are independently selected from: (i)substituted C₁₋₆ alkyl; (ii) substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy,or substituted C₃₋₆ alkenyloxy; (iii) substituted C₁₋₆ alkyl-amino,di(substituted C₁₋₆ alkyl)amino; (iv) C₃₋₆ alkenyl-amino, di(C₃₋₆alkenyl)amino, substituted C₃ (alkenyl-amino, or di(substituted C₃₋₆alkenyl)amino; and (v) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy-C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆ alkenyl)piperazino;wherein the substituents for (i), (ii), (iii), (iv), and (v) areselected from the group consisting of: (a) hydroxy, C₁₋₆ alkoxy, or C₁₋₆alkylamino; (b) C₃₋₆ alkenyloxy, or C₃₋₆ alkenylamino; and (c)pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl,piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino,4-N—(C₁₋₆ alkoxy C₁₋₄ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆ alkyl)piperazino, or4-N—(C₁₋₆ alkylamino-C₃₋₆ alkenyl)piperazino; or R₂ and R₃ are takentogether to form an aryl group or substituted aryl, wherein thesubstituents are defined as above in (i)-(V); and R₄ is selected fromthe group consisting of: (i) hydrogen; (ii) substituted C₁₋₁₁ alkyl orC₂₋₁₁ alkenyl wherein the substituents are independently selected fromthe group consisting of hydrogen, hydroxy, C₁₋₆ alkyloxy, C₁₋₆alkylthio,C₁₋₆ alkylamino, phenyl-C₁₋₆ alkylamino, and C₁₋₆ alkoxycarbonyl; and(iii) substituted aryl C₀₋₁₁ alkyl wherein the aryl group is selectedfrom phenyl, imidazolyl, furyl, and thienyl in which the substituentsare selected from the group consisting of: (a) hydroxy, C₁₋₆ alkoxy, orC₁₋₆ alkylamino; (b) C₃₋₆ alkenyloxy, or C₃₋₆ alkenylamino; and (c)pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl,piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino,4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆ alkyl)piperazino, or4-N—(C₁₋₆ alkylamino-C₃₋₆ alkenyl)piperazino; or (B) R₁ is selected fromthe group consisting of: mono-, di-, and tri-substituted aryl-C₀₋₆ alkylwherein aryl is selected from the group consisting of phenyl andthienyl, and the substituents are selected from the group consisting of:(i) trans-2-substituted benzimidazolylethenyl, trans-2-substitutedbenzoxazolylethenyl, or trans-2-substituted benzthiazolylethenyl,wherein the substituents are selected from the group consisting ofhydrogen, hydroxy, halo, trihalomethyl, C₁₋₄ alkyl, C₁₋₄ alkyloxy, C₁₋₄alkyloxycarbonyl, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₃₋₆alkenylamino, di(C₃₋₆ alkenyl)amino, C₁₋₄ alkyloxy-C₁₋₄ alkylamino,substituted C₁₋₄ alkyl, substituted C₁₋₄ alkyloxy, substituted C₁₋₄alkyloxycarbonyl, substituted C₁₋₄ alkylamino, di(substituted C₁₋₄alkyl)amino, substituted C₃₋₆ alkenylamino, and di(substituted C₃₋₆alkenyl)amino, wherein the substituents are selected from the groupconsisting of: (a) hydroxy, C₁₋₆ alkoxy, or C₁₋₆ alkylamino; (b) C₃₋₆alkenyloxy, or C₃₋₆ alkenylamino; and (c) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N—C₁₋₆alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆alkylamino-C₁₋₆ alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆alkenyl)piperazino; (ii) trans-2-cyano ethenyl, trans-2-alkylsulfonylethenyl, trans-2-alkenylsulfonyl ethenyl, trans-2-substitutedalkylsulfonyl ethenyl, and trans-2-substituted alkenylsulfonyl ethenyl,wherein the substituents are selected from the group consisting of: (a)hydroxy, C₁₋₆ alkoxy, or C₁₋₆ alkylamino; (b) C₃₋₆ alkenyloxy, or C₃₋₆alkenylamino; and (c) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino-C₃₋₆ alkenyl)piperazino; (iii)C₁₋₆ CO₂R₅, trans-CH═CHCO₂R₅, C₁₋₆CONHR₅, or trans-CH═CHCONHR₅, whereinR₅ is C₁₋₆ alkoxy-C₂₋₆ alkyl, amino-C₂₋₆ alkyl, C₁₋₆ alkylamino-C₂₋₆alkyl, di(C₁₋₆ alkyl)amino-C₂₋₆ alkyl, C₁₋₆ alkylthio-C₂₋₆ alkyl,substituted C₁₋₆ alkoxy-C₂₋₆ alkyl, substituted C₁₋₆ alkylamino-C₂₋₄alkyl, di(substituted C₁₋₆ alkyl)amino-C₂₋₆ alkyl, or substituted C₁₋₆alkylthio-C₂₋₆ alkyl, wherein the substituents are selected from thegroup consisting of pyrrolidino, piperidino morpholino, piperazino,4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆alkoxy-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy-C₃₋₆ alkenyl)piperazino,4-N—(C₁₋₄ alkylamino-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino, imidazolyl, oxazolyl, and thiazolyl; (iv)C₁₋₆CONHR₅, or trans-CH═CHCONR₆R₇, wherein R₆ and R₇ are independentlyselected from the group consisting of C₁₋₆ alkyl, phenyl-C₁₋₆ alkyl,C₁₋₆ alkoxycarbonylmethyleneoxy, hydroxy-C₂₋₆ (alkyl, C₁₋₆ alkyloxy-C₂₋₆alkyl, amino-C₂₋₆ alkyl, C₁₋₆ alkylamino-C₂₋₆ alkyl, di(C₁₋₆alkyl)amino-C₂₋₆ alkyl, C₁₋₆ alkylthio-C₂₋₆ alkyl, substituted C₁₋₆alkoxy-C₂₋₆ alkyl, substituted C₁₋₆ alkylamino-C₂₋₆ alkyl,di(substituted C₁₋₆ alkyl)amino-C₁₋₆ alkyl, substituted C₁₋₆alkylthio-C₂₋₆ alkyl, wherein the substituents are selected from thegroup consisting of pyrrolidino, piperidino, morpholino, piperazino,4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxyC₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkoxy-C₃₋₆ alkenyl)piperazino,4-N—(C₁₋₆ alkylamino-C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆ alkylamino-C₃₋₆alkenyl)piperazino, imidazolyl, oxazolyl, and thiazolyl; (v)R₇—C(O)—C₁₋₆ alkyl or R₇—C(O)—C₂₋₆ alkenyl, wherein R₇ is defined asabove in [B(iv)]; (vi) HO—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇—O—C₁₋₆ alkyl-C₂₋₆alkenyl, R₇NH—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C(O)—O—C₁₋₆ alkyl-C₂₋₆alkenyl, R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, or R₇—C(O)—O—C₁₋₆alkyl-C₂₋₆ alkenyl, wherein R₆ and R₇ is defined as above in [B(iv)];and (vii) R₇—O—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl, R₇NH—C₀₋₃ alkyl-C₃₋₆cycloalk-1-yl, R₆R₇N—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl, R₇NH—C(O)—O—C₀₋₃C₃₋₆ cycloalk-1-yl, R₆R₇N—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl,R₇O—C(O)—O—C₀₋₃ alkyl-C₃₋₆ cycloalk-1-yl, R₇—C(O)—O—C₀₋₃ alkyl-C₃₋₆cycloalk-1-yl, R₇O—C(O)—Co-3 alkyl-C₃₋₆ cycloalk-1-yl, wherein R₇ and R₆are defined as above in [B(iv)]; R₂ and R₃ are each independentlyselected from the group consisting of: (viii) hydrogen, halo,trihalomethyl, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₂₋₆ alkenyl,substituted C₂₋₆ alkenyl, C₁₋₆ alkyloxy, substituted C₁₋₆ alkyloxy, C₃₋₆alkenyloxy, substituted C₃₋₆ alkenyloxy, C₁₋₆ alkylamino, substitutedC₁₋₆ alkylamino, C₃₋₆ alkenylamino, or substituted C₃₋₆ alkenylamino;and (ix) mono-, di-, or tri-substituted phenyl wherein the substituentsare independently selected from the group consisting of: (a) halo,trifluoromethyl, or substituted C₁₋₆ alkyl; (b) C₁₋₆ alkyloxy,substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy, substituted C₃₋₆ alkenyloxy;(c) C₁₋₆ alkyl-amino, di(C₁₋₆ alkyl)amino, substituted C₁₋₆ alkyl-amino,di(substituted C₁₋₆ alkyl)amino, C₃₋₆ alkenyl-amino, di(C₃₋₆alkenyl)amino, substituted C₃₋₆ alkenyl-amino, or di(substituted C₃₋₆alkenyl)amino; and (d) pyrrolidino, piperidino, morpholino, imidazolyl,substituted imidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino;wherein the substituents for (a), (b), (c), and (d) are selected fromthe group consisting of: (1) hydrogen, hydroxy, halo, ortrifluoromethyl; (2) C₁₋₆ alkylalkoxy, C₁₋₆ alkylamino, or C₁₋₆alkylthio; (3) C₃₋₆ alkenyloxy, C₃₋₆ alkenylamino, or C₃₋₆ alkenylthio;and (4) pyrrolidino, piperidino, morpholino, imidazolyl, substitutedimidazolyl, piperazino, 4-N—C₁₋₆ alkylpiperazino, 4-N—C₃₋₆alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆ alkyl)piperazino, 4-N—(C₁₋₆alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆ alkylamino C₁₋₆alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆ alkenyl)piperazino; withthe proviso that a) at least one of R₂ and R₃ is selected from [B (ix)]and wherein the substituents are selected from [B (ix) (b)-(d)] above;or b) R₂ and R₃ are taken together to form an optionally substitutedaryl group, wherein the substituents are defined as above in [B (ix)(a)-(d)]; and R₄ is selected from the group consisting of: (i) hydrogen;(ii) substituted C₁₋₁₁ alkyl or C₂₋₁₁ alkenyl wherein the substituentsare independently selected from the group consisting of: (a) hydrogen,hydroxy, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, C₁₋₆ alkylamino, phenyl-C₁₋₆alkylamino, or C₁₋₆ alkoxycarbonyl; (b) substituted C₁₋₆ alkyloxy, C₃₋₆alkenyloxy, or substituted C₃₋₆ alkenyloxy; (c) di(C₁₋₆ alkyl)amino,substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆ alkyl)amino, C₃₋₆alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆ alkenyl-amino, ordi(substituted C₃₋₆ alkenyl)amino; and (d) pyrrolidino, piperidino,morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N—C₁₋₆alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₄alkylamino C₁₋₆ alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆alkenylpiperazino; and (iii) aryl C₀₋₁₁ alkyl wherein the aryl group isselected from phenyl, imidazolyl, furyl, or thienyl.
 29. The method ofclaim 1, 2, 3, 4, 17, 18, 27 or 28 or the composition of claim 23 or 24wherein the compound of Formula 1 or 1a is a compound wherein R₁ isselected from the group consisting of mono-, di-, and tri-substitutedaryl-C₀₋₆ alkyl wherein aryl is selected from the group consisting ofphenyl and thienyl, and the substituents are selected from the groupconsisting of: (a) C₁₋₆ CO₂R₅, trans-CH═CHCO₂R₅, C₁₋₆CONHR₅, ortrans-CH═CHCONHR₅; (b) C₁₋₆CONR₆R₇, or trans-CH═CHCONR₆R₇; (c) R₇ C(O)C₁₋₆ alkyl or R₇ C(O)C₂₋₆ alkenyl; and (d) HO—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₇—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C₁₋₆alkyl-C₂₋₆ alkenyl, R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₆R₇N—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇O—C(O)—O—C₁₋₆ alkyl-C₁₋₆alkenyl, or R₇—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl.
 30. The method of claim1, 2, 3, 4, 17, 18, 27 or 28 or the composition of claim 23 or 24wherein the compound of Formula 1 or 1a is a compound wherein R₁ isselected from the group consisting of mono-, di-, and tri-substitutedaryl-C₀₋₆ alkyl wherein aryl is selected from the group consisting ofphenyl and thienyl, and the substituents are selected from the groupconsisting of: (a) C₁₋₆ CO₂R₅, trans-CH═CHCO₂R₅, C₁₋₆CONHR₅, ortrans-CH═CHCONHR₅; (b) C₁₋₆CONR₆R₇, or trans-CH═CHCONR₆R₇; (c) R₇ C(O)C₁₋₆ alkyl or R₇ C(O)C₂₋₆ alkenyl; and (d) HO—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₇—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C₁₋₆alkyl-C₂₋₆ alkenyl, R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₆R₇N—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆alkenyl, or R₇—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl.
 31. The method of claim1, 2, 3, 4, 17, 18, 27 or 28 or the composition of claim 23 or 24wherein the compound of Formula 1 or 1a is a compound wherein R₁ isselected from the group consisting of mono-, di-, and tri-substitutedaryl-C₀₋₆ alkyl wherein aryl is selected from the group consisting ofphenyl and thienyl, and the substituents are HO—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₇—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₆R₇N—C₁₋₆alkyl-C₂₋₆ alkenyl, R₇NH—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₆R₇N—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆alkenyl, or R₇—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl.
 32. The method of claim31 wherein R₁ is selected from the group consisting of mono-, di-, andtri-substituted aryl-C₀₋₆ alkyl wherein the aryl-C₀₋₆ alkyl isphenyl-C₀₋₆ alkyl.
 33. The method of claim 31 wherein R₁ is selectedfrom the group consisting of mono-, di-, and tri-substituted aryl-C₀₋₆alkyl wherein the aryl-C₀₋₆ alkyl is aryl.
 34. The method of claim 1, 2,3, 4, 17, 18, 27 or 28 or the composition of claim 23 or 24 wherein R₂and R₃ are each independently selected from the group consisting of:mono-, di-, and tri-substituted phenyl wherein the substituents areindependently selected from the group consisting of: (i) C₁₋₆ alkyloxy,substituted C₁₋₆ alkyloxy, C₃₋₆ alkenyloxy, or substituted C₃₋₆alkenyloxy; (ii) C₁₋₄ alkyl-amino, di(C₁₋₆ alkyl)amino, substituted C₁₋₆alkyl-amino, di(substituted C₁₋₆ alkyl)amino, C₃₋₆ alkenyl-amino,di(C₃₋₆ alkenyl)amino, substituted C₃₋₆ alkenyl-amino, or di(substitutedC₃₋₆ alkenyl)amino, and (iii) pyrrolidino, piperidino, morpholino,imidazolyl, substituted imidazolyl, piperazino, 4-N—C₁₋₆alkylpiperazino, 4-N—C₃₋₆ alkenylpiperazino, 4-N—(C₁₋₆ alkoxy C₁₋₆alkyl)piperazino, 4-N—(C₁₋₆ alkoxy C₃₋₆ alkenyl)piperazino, 4-N—(C₁₋₆alkylamino C₁₋₆ alkyl)piperazino, or 4-N—(C₁₋₆ alkylamino C₃₋₆alkenyl)piperazino.
 35. The method of claim 1, 2, 3, 4, 17, 18, 27 or 28or the composition of claim 23 or 24 wherein R₂ and R₃ are eachindependently selected from the group consisting of: mono-, di-, andtri-substituted phenyl wherein the substituents are independentlyselected from the group consisting of C₁₋₆ alkyl-amino, di(C₁₋₆alkyl)amino, substituted C₁₋₆ alkyl-amino, di(substituted C₁₋₆alkyl)amino, C₃₋₆ alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆alkenyl-amino, and di(substituted C₃₋₆ alkenyl)amino.
 36. The method ofclaim 1, 2, 3, 4, 17, 18, 27 or 28 or the composition of claim 23 or 24wherein the compound of Formula 1 or 1a is a compound of Formula 1b:

wherein each instance of R₈ is independently C₁₋₆ alkyl-amino, di(C₁₋₆alkyl)amino, substituted C₁₋₄ alkyl-amino, di(substituted C₁₋₆alkyl)amino, C₃₋₆ alkenyl-amino, di(C₃₋₆ alkenyl)amino, substituted C₃₋₆alkenyl-amino, or di(substituted C₃₋₆ alkenyl)amino; and R_(b) isHO—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH—C₁₋₆alkyl-C₂₋₆ alkenyl, R₆R₇N—C₁₋₆ alkyl-C₂₋₆ alkenyl, R₇NH—C(O)—O—C₁₋₆alkyl-C₂₋₆ alkenyl, R₆R₇N—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl,R₇O—C(O)—O—C₁₋₆ alkyl-C₂₋₆ alkenyl, or R₇—C(O)—O—C₁₋₆ alkyl-C₂₋₆alkenyl.
 37. The method of claim 1, 2, 3, 4, 17, 18, 27 or 28 or thecomposition of claim 23 or 24 wherein R₄ is hydrogen.